Anilinopyrimidines as haematopoietic progenitor kinase 1 (hpk1) inhibitors

ABSTRACT

The invention relates to HPK 1  inhibitors useful in the treatment of cancers, and other serine-threonine kinase mediated diseases, having the Formula: where A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , R 17 , X 1 , X 2 , X 3 , X 4 , m, and n are described herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 62/428,191 filed on Nov. 30, 2016, the entirety of which ishereby incorporated by reference.

FIELD OF INVENTION

The present invention is directed to inhibitors of haematopoieticprogenitor kinase 1 (HPK1) useful in the treatment of diseases ordisorders associated with HPK1. Specifically, the invention is concernedwith compounds and compositions inhibiting HPK1, methods of treatingdiseases or disorders associated with HPK1, and methods of synthesis ofthese compounds.

BACKGROUND OF THE INVENTION

Cancer immunotherapy is treatment that uses the human body's own immunesystem to help fight cancer. This unique approach has witnessedsignificant clinical successes in the treatment of a variety of tumortypes in recent years, particularly with the application of immunecheckpoint inhibitors and chimeric antigen T cell therapy. Two of themost investigated checkpoint blockades (i.e., CTLA4 and PD-1 inhibitors)have demonstrated remarkable antitumor activity by overcomingimmunosuppressive mechanisms at the tumor site. CTLA4 blockadepredominantly enhances T cell activation during the priming phase of theimmune response, whereas PD-1 inhibitors appear to release exhausted butotherwise activated effector T cell populations and reduce regulatory Tcell function. While these monoclonal antibody-based T cellinterventions have proven to be effective, utility of this approach islimited as they can only target receptors on the cell surface. To thecontrary, small-molecule T cell activators offer the opportunity totarget both extracellular and intracellular immune targets includingkinases. Furthermore, inhibiting immune suppressive kinases has thepotential to directly activate T cells, thus bypassing checkpointinhibitory pathways and overcoming intrinsic and acquired resistance tocheckpoint receptor blockade.

Haematopoietic progenitor kinase 1 (HPK1; also known as MAP4K1) is amember of the germinal center kinase family of serine/threonine kinasesand is mainly expressed by haematopoietic cells. In T cells, it isbelieved that HPK1 phosphorylates serine 376 of SLP76 after T cellreceptor (TCR) triggers and induces the association of SLP76 with 14-3-3proteins. Knockdown of HPK1 expression in Jurkat T cells has been shownto increase TCR-induced activation of the IL2 gene. Further,antigen-stimulated T cells from HPK1-deficient mice proliferated morevigorously and produced higher amounts of cytokines as compared toantigen-stimulated T-cells from wild-type mice. Importantly,HPK1-deficient mice developed a more severe form of experimentalautoimmune encephalomyelitis (EAE), a model of multiple sclerosis. Bothin vitro and in vivo, HPK1 knockout dendritic cells (DC) havedemonstrated enhanced antigen presentation function. Particularly, bothHPK1 knockout T cells and HPK1 knockout DCs have been implicated intumor rejection in a murine model of lung cancer. These findings havevalidated HPK1 as a novel target for anti-cancer immunotherapy.Inhibition of HPK1 with small molecule inhibitors therefore has thepotential to be a treatment for cancers and other disorders.

SUMMARY OF THE INVENTION

The present disclosure provides novel2-(2,4,5-substituted)anilinopyrimidine compounds and pharmaceuticallyacceptable salts as effective HPK1 inhibitors and T cell activators.

A first aspect of the invention relates to compounds of Formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, and tautomer thereof,

wherein:

A is C₆₋₁₀ aryl or 5- or 6-membered heteroaryl;

X₁ is N or CH;

X₂ is N or CH;

X₃ is CR₇R₈, NH, O, or S(O)_(q);

X₄ is NR₉, O, S(O)_(q) or CR₁₀R₁₁;

R₁ is —P(O)R₁₂R₁₃;

R₂ is H, D, halogen, OH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₆₋₁₀ aryl, 5- to 7-membered heteroaryl, C₃₋₇ cycloalkyl, 3- to7-membered heterocycloalkyl, CN, NO₂, NR₁₄R₁₅, C(O)NR₁₄R₁₅, C(O)OR₁₄, orNR₁₄C(O)R₁₂, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₆₋₁₀ aryl, and 5- to 7-membered heteroaryl are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆ alkyl,

C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH;

R₃ is H, D, halogen, OH, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, or NR₁₄R₁₅ wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ alkoxy are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅,CN, NO₂, and OH;

R₄ is H, D, halogen, OH, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, or NR₁₄R₁₅ wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅,CN, NO₂, and OH; or

R₃ and R₄, together with the carbon atoms to which they are attached,form a C₅₋₇ cycloalkyl optionally substituted with one or more R₁₈; orR₃ and R₄, together with the carbon atoms to which they are attached,form a 5- to 7-membered heterocycloalkyl ring optionally substitutedwith one or more R₁₈; or R₃ and R₄, together with the carbon atoms towhich they are attached, form a C₆₋₁₀ aryl ring optionally substitutedwith one or more R₁₈; or R₃ and R₄, together with the carbon atoms towhich they are attached, form a 5- to 7-membered heteroaryl ringoptionally substituted with one or more R₁₈;

R₅ and R₆ are each independently H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, NH₂, C₁₋₆alkylamino, or C₁₋₆ dialkylamino, wherein the

C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, and 3- to7-membered heterocycloalkyl are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH; or

R₅ and R₆ together with the carbon atom to which they are attached forman oxo group; or R₅ and R₆ together with the carbon atom to which theyare attached form a C₃₋₇ cycloalkyl; or R₅ and R₆ together with thecarbon atom to which they are attached form a 3- to 7-memberedheterocycloalkyl ring;

R₇ and R₈ are each independently H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl,

C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, orNH₂, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,C₃₋₇ cycloalkyl, and heterocycloalkyl are optionally substituted withone or more substituents independently selected from the groupconsisting ofC₁₋₆ alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH; or

R₇ and R₈, together with the carbon atom to which they are attached,form a C₅₋₇ cycloalkyl ring optionally substituted with one or more R₁₉;or R₇ and R₈, together with the carbon atom to which they are attached,form a 5- to 7-membered heterocycloalkyl ring optionally substitutedwith one or more R₁₉; or R₇ and R₈, together with the carbon atom towhich they are attached, form a C₆₋₁₀ aryl ring optionally substitutedwith one or more R₁₉; or R₇ and R₈, together with the carbon atom towhich they are attached, form a 5- to 7-membered heteroaryl ringoptionally substituted with one or more R₁₉;

R₉ is H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —C(O)R₁₂, C₃₋₇cycloalkyl, or 3- to 7-membered heterocycloalkyl, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, and 3- to 7-memberedheterocycloalkyl are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, halogen, NR₁₄R₁₅, CN, NO₂, andOH;

R₁₀ and R₁₁ are each independently H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, NR₁₄R₁₅,

C₃₋₇ cycloalkyl, or 3- to 7-membered heterocycloalkyl, wherein C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, and heterocycloalkylare optionally substituted with one or more substituents independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆hydroxyalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH;

R₁₂ and R₁₃ are each independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₇ cycloalkyl,or 3- to 7-membered heterocycloalkyl; or

R₁₂ and R₁₃ together with the phosphorus atom to which they are attachedform a 3-8 membered heterocycloalkyl ring;

R₁₄ and R₁₅ are each independently H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, or 5- to 7-memberedheterocycloalkyl; or

R₁₄ and R₁₅ together with the nitrogen atom to which they are attachedform a 3- to 8-membered heterocycloalkyl ring optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, halogen,NR₁₆R₁₇, CN, NO₂, and OH;

R₁₆ and R₁₇ are each independently H, D, or C₁₋₆ alkyl;

each R₁₈ is independently selected from the group consisting of halogen,OH, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, and NR₁₄R₁₅;

each R₁₉ is independently selected from the group consisting of halogen,OH, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, and NR₁₄R₁₅;

R₂₀ and R₂₁ are each independently H, D, or C₁₋₆ alkyl; or

R₂₀ and R₉, when on adjacent atoms, together with the atoms to whichthey are attached form a 5- to 7-membered heterocycloalkyl ring;

each m and n is independently 0, 1, or 2, wherein the sum of m and n is0, 1, or 2; and

q is 0, 1, or 2.

A second aspect of the invention relates to a method of treating aHPK1-mediated disease or disorder. The method comprises administering toa patient in need thereof an effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of preventing aHPK1-mediated disease or disorder. The method comprises administering toa patient in need thereof an effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of inhibiting HPK1.The method comprises administering to a patient in need thereof aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

Another aspect of the invention relates to a method of treating adisease or disorder associated with inhibiting HPK1. The methodcomprises administering to a patient in need thereof an effective amountof a compound of Formula (I), or a pharmaceutically acceptable salt,hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of preventing adisease or disorder associated with inhibiting HPK1. The methodcomprises administering to a patient in need thereof an effective amountof a compound of Formula (I), or a pharmaceutically acceptable salt,hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of treating aHPK1-mediated disease or disorder comprising administering to a patientin need of a treatment for a HPK1-mediated disease or disorder aneffective amount of a compound of Formula (II), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof,

wherein:

R₁ is C₁₋₆ alkoxy, CN, NO₂, C(O)NR₁₄R₁₅, SO₂R₁₄, SO₂NR₁₄R₁₅, C(O)R₁₄, orNR₁₆C(O)R₁₄;

R₂ is halogen;

R₃ is C₁₋₆ alkoxy;

R₄ is H or C₁₋₆ alkyl;

R₁₄ and R₁₅ are each independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, or 3- to 7-memberedheterocycloalkyl; or

R₁₄ and R₁₅ together with the nitrogen atom to which they are attachedform a 3- to 8-membered heterocycloalkyl ring optionally substitutedwith one or more substituents each independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, halogen,NR₁₆R₁₇, CN, NO₂, and OH; and

R₁₆ and R₁₇ are each independently H or C₁₋₆ alkyl.

Another aspect of the invention relates to a method of preventing aHPK1-mediated disease or disorder comprising administering to a patientin need thereof an effective amount of a compound of Formula (II), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

Another aspect of the invention is directed to a method of inhibitingHPK1. The method involves administering to a patient in need thereof aneffective amount of a compound of Formula (II), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

Another aspect of the invention relates to a method of treating adisease or disorder associated with inhibiting HPK1. The methodcomprises administering to a patient in need thereof an effective amountof a compound of Formula (II), or a pharmaceutically acceptable salt,hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of preventing adisease or disorder associated with inhibiting HPK1. The methodcomprises administering to a patient in need thereof an effective amountof a compound of Formula (II), or a pharmaceutically acceptable salt,hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of treating cancer.The method comprises administering to a patient in need thereof aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

Another aspect of the invention relates to a method of treating cancer.The method comprises administering to a patient in need thereof aneffective amount of a compound of Formula (II), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof and a pharmaceutically acceptable carrier. The pharmaceuticalacceptable carrier may further include an excipient, diluent, orsurfactant.

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula (II), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof and a pharmaceutically acceptablecarrier. The pharmaceutical acceptable carrier may further include anexcipient, diluent, or surfactant.

Another aspect of the present invention relates to a compound of Formula(I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the manufacture of amedicament for treating a disease associated with inhibiting HPK1.

Another aspect of the present invention relates to a compound of Formula(II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the manufacture of amedicament for treating a disease associated with inhibiting HPK1.

Another aspect of the present invention relates to a compound of Formula(I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the manufacture of amedicament for preventing a disease associated with inhibiting HPK1.

Another aspect of the present invention relates to a compound of Formula(II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the manufacture of amedicament for preventing a disease associated with inhibiting HPK1.

Another aspect of the present invention relates to the use of a compoundof Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, in the treatment of adisease associated with inhibiting HPK1.

Another aspect of the present invention relates to the use of a compoundof Formula (II), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment ofa disease associated with inhibiting HPK1.

Another aspect of the present invention relates to the use of a compoundof Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, in the prevention of adisease associated with inhibiting HPK1.

Another aspect of the present invention relates to the use of a compoundof Formula (II), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof, in the preventionof a disease associated with inhibiting HPK1.

The present invention further provides methods of treating or preventinga disease or disorder associated with modulation of HPK1 including,cancer, metastasis, inflammation and auto-immune pathogenesis,comprising administering to a patient suffering from at least one ofsaid diseases or disorder a compound of Formula (I), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

The present invention provides inhibitors of HPK1 that are therapeuticagents in the treatment of diseases such as cancer, metastasis,inflammation and auto-immune pathogenesis.

The present disclosure provides agents with novel mechanisms of actiontoward HPK1 enzymes in the treatment of various types of diseasesincluding cancer, metastasis, inflammation and auto-immune pathogenesis.Ultimately the present invention provides the medical community with anovel pharmacological strategy for the treatment of diseases anddisorders associated with HPK1.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds and compositions that arecapable of inhibiting the activity of HPK1. The invention featuresmethods of treating, preventing or ameliorating a disease or disorder inwhich HPK1 plays a role by administering to a patient in need thereof atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof. The invention also features methodsof treating, preventing or ameliorating a disease or disorder in whichHPK1 plays a role by administering to a patient in need thereof atherapeutically effective amount of a compound of Formula (II), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof. The methods of the present inventioncan be used in the treatment of a variety of HPK1 dependent diseases anddisorders by inhibiting the activity of HPK1 enzymes. Inhibition of HPK1provides a novel approach to the treatment, prevention, or ameliorationof diseases including, but not limited to, cancer and metastasis.

In a first aspect of the invention, the compounds of Formula (I) aredescribed:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof, wherein A, R₁, R₂, R₃, R₄, R₅, R₆,R₁₆, R₁₇, R₂₀, R₂₁, X₁, X₂, X₃, X₄, m, and n are as described hereinabove.

The details of the invention are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, illustrative methods and materials are now described.Other features, objects, and advantages of the invention will beapparent from the description and from the claims. In the specificationand the appended claims, the singular forms also include the pluralunless the context clearly dictates otherwise. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs. All patents and publications cited in thisspecification are incorporated herein by reference in their entireties.

Definitions

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

The term “optionally substituted” is understood to mean that a givenchemical moiety (e.g., an alkyl group) can (but is not required to) bebonded other substituents (e.g., heteroatoms). For instance, an alkylgroup that is optionally substituted can be a fully saturated alkylchain (i.e., a pure hydrocarbon). Alternatively, the same optionallysubstituted alkyl group can have substituents different from hydrogen.For instance, it can, at any point along the chain be bounded to ahalogen atom, a hydroxyl group, or any other substituent describedherein. Thus the term “optionally substituted” means that a givenchemical moiety has the potential to contain other functional groups,but does not necessarily have any further functional groups. Suitablesubstituents used in the optional substitution of the described groupsinclude, without limitation, halogen, oxo, —OH, —CN, —COOH, —CH₂CN,—O—(C₁-C₆) alkyl, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl,(C₁-C₆) haloalkoxy, —O—(C₂-C₆) alkenyl, —O—(C₂-C₆) alkynyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, —OH, —OP(O)(OH)₂, —OC(O)(C₁-C₆) alkyl,—C(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆) alkyl, —NH₂, —NH((C₁-C₆) alkyl),—N((C₁-C₆) alkyl)₂, —NHC(O)(C₁-C₆) alkyl, —C(O)NH(C₁-C₆) alkyl,—S(O)₂(C₁-C₆) alkyl, —S(O)NH(C₁-C₆) alkyl, and S(O)N((C₁-C₆) alkyl)₂.The substituents can themselves be optionally substituted. “Optionallysubstituted” as used herein also refers to substituted or unsubstitutedwhose meaning is described below.

As used herein, the term “substituted” means that the specified group ormoiety bears one or more suitable substituents wherein the substituentsmay connect to the specified group or moiety at one or more positions.For example, an aryl substituted with a cycloalkyl may indicate that thecycloalkyl connects to one atom of the aryl with a bond or by fusingwith the aryl and sharing two or more common atoms.

Unless otherwise specifically defined, the term “aryl” refers to cyclic,aromatic hydrocarbon groups that have 1 to 3 aromatic rings, includingmonocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl.Where containing two aromatic rings (bicyclic, etc.), the aromatic ringsof the aryl group may be joined at a single point (e.g., biphenyl), orfused (e.g., naphthyl). The aryl group may be optionally substituted byone or more substituents, e.g., 1 to 5 substituents, at any point ofattachment. Exemplary substituents include, but are not limited to, —H,-halogen, —O—(C₁-C₆) alkyl, (C₁-C₆) alkyl, —O—(C₂-C₆) alkenyl,—O—(C₂-C₆) alkynyl,

(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —OH, —OP(O)(OH)₂, —OC(O)(C₁-C₆) alkyl,—C(O)(C₁-C₆) alkyl,—OC(O)O(C₁-C₆) alkyl, NH₂, NH((C₁-C₆) alkyl), N((C₁-C₆) alkyl)₂,—S(O)₂—(C₁-C₆) alkyl, —S(O)NH(C₁-C₆) alkyl, and S(O)N((C₁-C₆) alkyl)₂.The substituents can themselves be optionally substituted. Furthermorewhen containing two fused rings the aryl groups herein defined may havean unsaturated or partially saturated ring fused with a fully saturatedring. Exemplary ring systems of these aryl groups include, but are notlimited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl,phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl,tetrahydrobenzoannulenyl, and the like.

Unless otherwise specifically defined, “heteroaryl” means a monovalentmonocyclic aromatic radical of 5 to 24 ring atoms or a polycyclicaromatic radical, containing one or more ring heteroatoms selected fromN, O, or S, the remaining ring atoms being C. Heteroaryl as hereindefined also means a bicyclic heteroaromatic group wherein theheteroatom is selected from N, O, or S. The aromatic radical isoptionally substituted independently with one or more substituentsdescribed herein. Examples include, but are not limited to, furyl,thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl,isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl,quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole,benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl,imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl,indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl,pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl,thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl,indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl,benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl,dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl,1,6-naphthyridinyl, benzo[de]isoquinolinyl,pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl,tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl,pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl,pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl,3,4-dihydro-2H-1λ²-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d] thiophene,pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl,1H-pyrido[3,4-b][1,4] thiazinyl, benzooxazolyl, benzoisoxazolyl,furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl,furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl,[1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one,3,4-dihydro-2H-pyrazolo [1,5-b][1,2]oxazinyl,4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl,imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl,and derivatives thereof. Furthermore when containing two fused rings thearyl groups herein defined may have an unsaturated or partiallysaturated ring fused with a fully saturated ring. Exemplary ring systemsof these heteroaryl groups include indolinyl, indolinonyl,dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl,tetrahydroquinolinyl, dihydrobenzothiazine,3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl,and dihydrobenzoxanyl.

Halogen or “halo” refers to fluorine, chlorine, bromine, or iodine.

Alkyl refers to a straight or branched chain saturated hydrocarboncontaining 1-12 carbon atoms. Examples of a (C₁-C₆) alkyl group include,but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl,isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, andisohexyl.

“Alkoxy” refers to a straight or branched chain saturated hydrocarboncontaining 1-12 carbon atoms containing a terminal “O” in the chain,i.e., —O(alkyl). Examples of alkoxy groups include, without limitation,methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

“Alkenyl” refers to a straight or branched chain unsaturated hydrocarboncontaining 2-12 carbon atoms. The “alkenyl” group contains at least onedouble bond in the chain. The double bond of an alkenyl group can beunconjugated or conjugated to another unsaturated group. Examples ofalkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl,pentenyl, or hexenyl. An alkenyl group can be unsubstituted orsubstituted. Alkenyl, as herein defined, may be straight or branched.

“Alkynyl” refers to a straight or branched chain unsaturated hydrocarboncontaining 2-12 carbon atoms. The “alkynyl” group contains at least onetriple bond in the chain. Examples of alkenyl groups include ethynyl,propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. An alkynylgroup can be unsubstituted or substituted.

“Cycloalkyl” means monocyclic saturated carbon rings containing 3-18carbon atoms. Examples of cycloalkyl groups include, withoutlimitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptanyl, cyclooctanyl, norboranyl, norborenyl,bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

“Heterocyclyl” or “heterocycloalkyl” monocyclic rings containing carbonand heteroatoms taken from oxygen, nitrogen, or sulfur and wherein thereis not delocalized 7 electrons (aromaticity) shared among the ringcarbon or heteroatoms. The heterocycloalkyl ring structure may besubstituted by one or more substituents. The substituents can themselvesbe optionally substituted. Examples of heterocyclyl rings include, butare not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl,tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl,thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl,piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide,thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl,tropanyl, oxazolidinonyl, and homotropanyl.

The term “hydroxyalkyl” means an alkyl group as defined above, where thealkyl group is substituted with one or more —OH groups. Examples ofhydroxyalkyl groups include HO—CH₂—, HO—CH₂—CH₂— and CH₃—CH(OH)—.

The term “haloalkyl” as used herein refers to an alkyl group, as definedherein, which is substituted one or more halogen. Examples of haloalkylgroups include, but are not limited to, trifluoromethyl, difluoromethyl,pentafluoroethyl, trichloromethyl, etc.

The term “haloalkoxy” as used herein refers to an alkoxy group, asdefined herein, which is substituted one or more halogen. Examples ofhaloalkyl groups include, but are not limited to, trifluoromethoxy,difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

The term “amine” as used herein refers to primary (R—NH₂, R≠H),secondary (R₂—NH, R₂≠H) and tertiary (R₃—N, R≠H) amines. A substitutedamine is intended to mean an amine where at least one of the hydrogenatoms has been replaced by the substituent.

The term “amino” as used herein means a substituent containing at leastone nitrogen atom. Specifically, NH₂, —NH(alkyl) or alkylamino,—N(alkyl)₂ or dialkylamino, amide-, carbamide-, urea, and sulfamidesubstituents are included in the term “amino”.

The term “alkylamino” as used herein refers to an amino or NH₂ groupwhere one of the hydrogens has been replaced with an alkyl group, asdefined herein above, i.e., —NH(alkyl). Example of alkylamino groupsinclude, but are not limited to, methylamino (i.e., —NH(CH₃)),ethylamino, propylamino, iso-propylamino, n-butylamino, sec-butylamino,tert-butylamino, etc.

The term “dialkylamino” as used herein refers to an amino or NH₂ groupwhere both of the hydrogens have been replaced with alkyl groups, asdefined herein above, i.e., —N(alkyl)₂. The alkyl groups on the aminogroup can be the same or different alkyl groups. Example of alkylaminogroups include, but are not limited to, dimethylamino (i.e., —N(CH₃)₂),diethylamino, dipropylamino, diiso-propylamino, di-n-butylamino,di-sec-butylamino, di-tert-butylamino, methyl(ethyl)amino,methyl(butylamino), etc.

The term “oxo” as used herein refers to an “═O” group.

The term “solvate” refers to a complex of variable stoichiometry formedby a solute and solvent. Such solvents for the purpose of the inventionmay not interfere with the biological activity of the solute. Examplesof suitable solvents include, but are not limited to, water, MeOH, EtOH,and AcOH. Solvates wherein water is the solvent molecule are typicallyreferred to as hydrates. Hydrates include compositions containingstoichiometric amounts of water, as well as compositions containingvariable amounts of water.

The term “isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers). Withregard to stereoisomers, the compounds of Formula (I) may have one ormore asymmetric carbon atom and may occur as racemates, racemic mixturesand as individual enantiomers or diastereomers.

The disclosure also includes pharmaceutical compositions comprising aneffective amount of a disclosed compound and a pharmaceuticallyacceptable carrier. Representative “pharmaceutically acceptable salts”include, e.g., water-soluble and water-insoluble salts, such as theacetate, amsonate (4,4-diaminostilbene-2,2-disulfonate),benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate,bromide, butyrate, calcium, calcium edetate, camsylate, carbonate,chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate,estolate, esylate, fumerate, fiunarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate,mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,mucate, napsylate, nitrate, N-methylglucamine ammonium salt,3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate(1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate,phosphate/diphosphate, picrate, polygalacturonate, propionate,p-toluenesulfonate, salicylate, stearate, subacetate, succinate,sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate,tosylate, triethiodide, and valerate salts.

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guineapig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

An “effective amount” when used in connection with a compound is anamount effective for treating or preventing a disease in a subject asdescribed herein.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body of a subject.

As used herein, “treating” or “treat” describes the management and careof a patient for the purpose of reversing, inhibiting, or combating adisease, condition, or disorder and includes the administration of acompound of the present disclosure (i.e., a compound of Formula (I) orFormula (II)), or a pharmaceutically acceptable salt, prodrug,metabolite, polymorph or solvate thereof, to reverse the disease,condition, or disorder, eliminate the disease, condition, or disorder,or inhibit the process of the disease, condition, or disorder.

A compound of the present disclosure (i.e., a compound of Formula (I) orFormula (II)), or a pharmaceutically acceptable salt, prodrug,metabolite, polymorph or solvate thereof, can also be used to prevent adisease, condition, or disorder or one or more symptoms of such disease,condition, or disorder. As used herein, “preventing” or “prevent”describes reducing or eliminating the onset of the symptoms orcomplications of the disease, condition, or disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The term “administer”, “administering”, or “administration” as used inthis disclosure refers to either directly administering a disclosedcompound or pharmaceutically acceptable salt of the disclosed compoundor a composition to a subject, or administering a prodrug derivative oranalog of the compound or pharmaceutically acceptable salt of thecompound or composition to the subject, which can form an equivalentamount of active compound within the subject's body.

The term “prodrug,” as used in this disclosure, means a compound whichis convertible in vivo by metabolic means (e.g., by hydrolysis) to adisclosed compound.

The present invention relates to compounds or pharmaceuticallyacceptable salts, hydrates, solvates, prodrugs, stereoisomers, ortautomers thereof, capable of inhibiting HPK1, which are useful for thetreatment of diseases and disorders associated with modulation of a HPK1enzyme. The invention further relates to compounds, or pharmaceuticallyacceptable salts, hydrates, solvates, prodrugs, stereoisomers, ortautomers thereof, which are useful for inhibiting HPK1.

In one embodiment, the compounds of Formula (I) have the structure ofFormula (Ia):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ib):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ic):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Id):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ie):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof.

In another embodiment, the compounds of Formula (I) have the structureof Formula (If):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ig):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ih):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ii):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ij):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ik):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof.

In some embodiments of the formulae above:

A is C₆₋₁₀ aryl or 5- or 6-membered heteroaryl;

X₁ is N or CH;

X₂ is N or CH;

X₃ is CR₇R₈, NH, O, or S(O)_(q);

X₄ is NR₉, O, S(O)_(q) or CR₁₀R₁₁;

R₁ is —P(O)R₁₂R₁₃;

R₂ is H, D, halogen, OH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₆₋₁₀ aryl, 5- to 7-membered heteroaryl, C₃₋₇ cycloalkyl, 3- to7-membered heterocycloalkyl, CN, NO₂, NR₁₄R₁₅, C(O)NR₁₄R₁₅, C(O)OR₁₄, orNR₁₄C(O)R₁₂, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₆₋₁₀ aryl, and 5- to 7-membered heteroaryl are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆ alkyl,

C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH;

R₃ is H, halogen, OH, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ alkoxy, C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, or NR₁₄R₁₅ wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ alkoxy are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅,CN, NO₂, and OH;

R₄ is H, halogen, OH, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ alkoxy, C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, or NR₁₄R₁₅ wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅,CN, NO₂, and OH; or

R₃ and R₄, together with the carbon atoms to which they are attached,form a C₅₋₇ cycloalkyl optionally substituted with one or more R₁₈; orR₃ and R₄, together with the carbon atoms to which they are attached,form a 5- to 7-membered heterocycloalkyl ring optionally substitutedwith one or more R₁₈; or R₃ and R₄, together with the carbon atoms towhich they are attached, form a C₆₋₁₀ aryl ring optionally substitutedwith one or more R₁₈; or R₃ and R₄, together with the carbon atoms towhich they are attached, form a 5- to 7-membered heteroaryl ringoptionally substituted with one or more R₁₈;

R₅ and R₆ are each independently H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, NH₂, C₁₋₆alkylamino, or C₁₋₆ dialkylamino, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl areoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl,halogen, NR₁₄R₁₅, CN, NO₂, and OH; or

R₅ and R₆ together with the carbon atom to which they are attached forman oxo group; or R₅ and R₆ together with the carbon atom to which theyare attached form a C₃₋₇ cycloalkyl; or R₅ and R₆ together with thecarbon atom to which they are attached form a 3- to 7-memberedheterocycloalkyl ring;

R₇ and R₈ are each independently H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, or NH₂,wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, andheterocycloalkyl are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH; or

R₇ and R₈, together with the carbon atom to which they are attached,form a C₅₋₇ cycloalkyl ring optionally substituted with one or more R₁₉;or R₇ and R₈, together with the carbon atom to which they are attached,form a 5- to 7-membered heterocycloalkyl ring optionally substitutedwith one or more R₁₉; or R₇ and R₈, together with the carbon atom towhich they are attached, form a C₆₋₁₀ aryl ring optionally substitutedwith one or more R₁₉; or R₇ and R₈, together with the carbon atom towhich they are attached, form a 5- to 7-membered heteroaryl ringoptionally substituted with one or more R₁₉;

R₉ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —C(O)R₁₂, C₃₋₇cycloalkyl, or 3- to 7-membered heterocycloalkyl, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, and 3- to 7-memberedheterocycloalkyl are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, halogen, NR₁₄R₁₅, CN, NO₂, andOH;

R₁₀ and R₁₁ are each independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, NR₁₄R₁₅, C₃₋₇ cycloalkyl, or 3- to 7-membered heterocycloalkyl,wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, andheterocycloalkyl are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, halogen, NR₁₄R₁₅, CN, NO₂, andOH;

R₁₂ and R₁₃ are each independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₇ cycloalkyl,or 3- to 7-membered heterocycloalkyl; or

R₁₂ and R₁₃ together with the phosphorus atom to which they are attachedform a 3-8 membered heterocycloalkyl ring;

R₁₄ and R₁₅ are each independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, or 5- to 7-memberedheterocycloalkyl; or

R₁₄ and R₁₅ together with the nitrogen atom to which they are attachedform a 3- to 8-membered heterocycloalkyl ring optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, halogen,NR₁₆R₁₇, CN, NO₂, and OH;

R₁₆ and R₁₇ are each independently H or C₁₋₆ alkyl;

each R₁₈ is independently selected from the group consisting of halogen,OH, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, and NR₁₄R₁₅;

each R₁₉ is independently selected from the group consisting of halogen,OH, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, and NR₁₄R₁₅;

R₂₀ and R₂₁ are each independently H or C₁₋₆ alkyl; or

R₂₀ and R₉, when on adjacent atoms, together with the atoms to whichthey are attached form a 5- to 7-membered heterocycloalkyl ring;

each m and n is independently 0, 1, or 2, wherein the sum of m and n is0, 1, or 2; and

q is 0, 1, or 2.

In some embodiments of the formulae above:

X₁ is N or CH;

X₂ is N or CH;

X₃ is CR₇R₈, NH, O, or S(O)_(q);

X₄ is NR₉, O, S(O)_(q) or CR₁₀R₁₁;

R₁ is —P(O)R₁₂R₁₃;

R₂ is H, halogen, OH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₆₋₁₀ aryl, 5- to 7-membered heteroaryl, C₃₋₇ cycloalkyl, 3- to7-membered heterocycloalkyl, CN, NO₂, NR₁₄R₁₅, C(O)NR₁₄R₁₅, C(O)OR₁₄, orNR₁₄C(O)R₁₂, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,

C₁₋₆ alkoxy, C₆₋₁₀ aryl, and 5- to 7-membered heteroaryl are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅,CN, NO₂, and OH;

R₃ is H, halogen, OH, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ alkoxy, C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, or NR₁₄R₁₅ wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ alkoxy are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅,CN, NO₂, and OH;

R₄ is H, halogen, OH, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ alkoxy, C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, or NR₁₄R₁₅ wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅,CN, NO₂, and OH; or

R₃ and R₄, together with the carbon atoms to which they are attached,form a C₅₋₇ cycloalkyl optionally substituted with one or more R₁₈; orR₃ and R₄, together with the carbon atoms to which they are attached,form a 5- to 7-membered heterocycloalkyl ring optionally substitutedwith one or more R₁₈; or R₃ and R₄, together with the carbon atoms towhich they are attached, form a C₆₋₁₀ aryl ring optionally substitutedwith one or more R₁₈; or R₃ and R₄, together with the carbon atoms towhich they are attached, form a 5- to 7-membered heteroaryl ringoptionally substituted with one or more R₁₈;

R₅ and R₆ are each independently H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, NH₂, C₁₋₆alkylamino, or C₁₋₆ dialkylamino, wherein the

C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, and 3- to7-membered heterocycloalkyl are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH; or

R₅ and R₆ together with the carbon atom to which they are attached forman oxo group; or R₅ and R₆ together with the carbon atom to which theyare attached form a C₃₋₇ cycloalkyl; or R₅ and R₆ together with thecarbon atom to which they are attached form a 3- to 7-memberedheterocycloalkyl ring;

R₇ and R₈ are each independently H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl,

C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, orNH₂, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore substituents independently selected from the group consisting ofC₁₋₆ alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH; or

R₇ and R₈, together with the carbon atom to which they are attached,form a C₅₋₇ cycloalkyl ring optionally substituted with one or more R₁₉;or R₇ and R₈, together with the carbon atom to which they are attached,form a 5- to 7-membered heterocycloalkyl ring optionally substitutedwith one or more R₁₉; or R₇ and R₈, together with the carbon atom towhich they are attached, form a C₆₋₁₀ aryl ring optionally substitutedwith one or more R₁₉; or R₇ and R₈, together with the carbon atom towhich they are attached, form a 5- to 7-membered heteroaryl ringoptionally substituted with one or more R₁₉;

R₉ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —C(O)R₁₂, C₃₋₇cycloalkyl, or 3- to 7-membered heterocycloalkyl, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, and 3- to 7-memberedheterocycloalkyl are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, halogen, NR₁₄R₁₅, CN, NO₂, andOH;

R₁₀ and R₁₁ are each independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, NR₁₄R₁₅, C₃₋₇ cycloalkyl, or 3- to 7-membered heterocycloalkyl,wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, andheterocycloalkyl are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, halogen, NR₁₄R₁₅, CN, NO₂, andOH;

R₁₂ and R₁₃ are each independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₇ cycloalkyl,or 3- to 7-membered heterocycloalkyl; or

R₁₂ and R₁₃ together with the phosphorus atom to which they are attachedform a 3-8 membered heterocycloalkyl ring;

R₁₄ and R₁₅ are each independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, or 5- to 7-memberedheterocycloalkyl; or

R₁₄ and R₁₅ together with the nitrogen atom to which they are attachedform a 3- to 8-membered heterocycloalkyl ring optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, halogen,NR₁₆R₁₇, CN, NO₂, and OH;

R₁₆ and R₁₇ are each independently H or C₁₋₆ alkyl;

each R₁₈ is independently selected from the group consisting of halogen,OH, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, and NR₁₄R₁₅;

each R₁₉ is independently selected from the group consisting of halogen,OH, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, and NR₁₄R₁₅;

each m and n is independently 0, 1, or 2, wherein the sum of m and n is0, 1, or 2; and

q is 0, 1, or 2.

In some embodiments of the Formulae above, A is C₆₋₁₀ aryl. In anotherembodiment, A is 5- or 6-membered heteroaryl. In yet another embodiment,A is 5-membered heteroaryl. In another embodiment, A is 6-memberedheteroaryl. In yet another embodiment, A is phenyl.

In some embodiments of the Formulae above, X₁ is N. In anotherembodiment, X₁ is CH.

In some embodiments of the Formulae above, X₂ is N. In anotherembodiment, X₂ is CH.

In some embodiments of the Formulae above, X₃ is CR₇R₈, NH, or O. Inanother embodiment, X₃ is NH, O, or S(O)_(q). In yet another embodiment,X₃ is CR₇R₈, O, or S(O)_(q). In another embodiment, X₃ is CR₇R₈, NH, orS(O)_(q). In yet another embodiment, X₃ is CR₇R₈ or NH. In anotherembodiment, X₃ is CR₇R₈ or O. In yet another embodiment, X₃ is CR₇R₈ orS(O)_(q). In another embodiment, X₃ is NH or O. In yet anotherembodiment, X₃ is NH or S(O)_(q). In another embodiment, X₃ is O orS(O)_(q). In yet another embodiment, X₃ is CR₇R₈.

In some embodiments of the Formulae above, X₄ is NR₉, O, or S(O)_(q). Inanother embodiment, X₄ is O, S(O)_(q) or CR₁₀R₁₁. In yet anotherembodiment, X₄ is NR₉, S(O)_(q) or CR₁₀R₁₁. In another embodiment, X₄ isNR₉, O, or CR₁₀R₁₁. In yet another embodiment, X₄ is NR₉ or O. Inanother embodiment, X₄ is O or S(O)_(q). In yet another embodiment, X₄is S(O)_(q) or CR₁₀R₁₁. In another embodiment, X₄ is NR₉ or S(O)_(q). Inyet another embodiment, X₄ is NR₉ or CR₁₀R₁₁. In another embodiment, X₄is O or CR₁₀R₁₁. In yet another embodiment, X₄ is NR₉. In anotherembodiment, X₄ is CR₁₀R₁₁.

In some embodiments of the Formulae above, R₂ is H, halogen, OH, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₆₋₁₀ aryl, 5- to7-membered heteroaryl, C₃₋₇ cycloalkyl, 3- to 7-memberedheterocycloalkyl, CN, NO₂, NR₁₄R₁₅, C(O)NR₁₄R₁₅, C(O)OR₁₄, orNR₁₄C(O)R₁₂, wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄alkoxy, C₆₋₁₀ aryl, and 5- to 7-membered heteroaryl are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅,CN, NO₂, and OH. In another embodiment, R₂ is halogen, OH, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₆₋₁₀ aryl, 5- to 7-memberedheteroaryl, C₃₋₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, CN, NO₂,NR₁₄R₁₅, C(O)NR₁₄R₁₅, C(O)OR₁₄, or NR₁₄C(O)R₁₂, wherein the C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and 5- to7-membered heteroaryl are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH.

In another embodiment, R₂ is H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄alkoxy, C₆₋₁₀ aryl, or 5- to 7-membered heteroaryl, wherein the C₁₋₄alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and 5- to 7-memberedheteroaryl are optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH. In another embodiment, R₂is halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, C₆₋₁₀ aryl, or 5- to7-membered heteroaryl, wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄alkoxy, C₆₋₁₀ aryl, and 5- to 7-membered heteroaryl are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅,CN, NO₂, and OH. In another embodiment, R₂ is H, halogen, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₁₋₄ alkoxy, or 5- to 7-membered heteroaryl, wherein theC₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, and 5- to 7-membered heteroarylare optionally substituted with one or more substituents independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl,halogen, NR₁₄R₁₅, CN, NO₂, and OH. In another embodiment, R₂ is H,halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, or 5- to 7-memberedheteroaryl, wherein the C₁₋₄ alkyl, is optionally substituted with oneor more halogen. In another embodiment, R₂ is halogen. In anotherembodiment, R₂ is F, Cl or Br. In another embodiment, R₂ is Cl.

In some embodiments of the Formulae above, R₃ is H, halogen, OH, CN,NO₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C(O)NR₁₄R₁₅,NR₁₄C(O)R₁₂, or NR₁₄R₁₅ wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, and C₁₋₄ alkoxy are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH. In anotherembodiment, R₃ is halogen, OH, CN, NO₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ alkoxy, C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, or NR₁₄R₁₅ wherein theC₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₁₋₄ alkoxy are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅,CN, NO₂, and OH. In another embodiment, R₃ is H, halogen, C₁₋₄ alkyl,C₂₋₄ alkenyl, or C₁₋₄ alkoxy, wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, andC₁₋₄ alkoxy are optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH. In another embodiment, R₃is H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, or C₁₋₄ alkoxy. In anotherembodiment, R₃ is H, halogen, C₁₋₃ alkyl, C₂₋₃ alkenyl, or C₁₋₃ alkoxy.

In some embodiments of the Formulae above, R₄ is H, halogen, OH, CN,NO₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C(O)NR₁₄R₁₅,NR₁₄C(O)R₁₂, or NR₁₄R₁₅, wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ alkoxy are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH. In anotherembodiment, R₄ is halogen, OH, CN, NO₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ alkoxy, C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, or NR₁₄R₁₅, wherein theC₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅,CN, NO₂, and OH. In another embodiment, R₄ is H, halogen, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₁₋₄ alkoxy, C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, or NR₁₄R₁₅, whereinthe C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy are optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, andOH. In another embodiment, R₄ is H, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, or NR₁₄R₁₅, wherein the C₁₋₄ alkyl, C₁₋₄alkoxy are optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH. In another embodiment, R₄is H, halogen, C₁₋₄ alkyl, or NR₁₄R₁₅, wherein the C₁₋₄ alkyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl,halogen, NR₁₄R₁₅, CN, NO₂, and OH. In another embodiment, R₄ is H,halogen, or NR₁₄R₁₅.

In some embodiments of the Formulae above, R₃ and R₄, together with thecarbon atoms to which they are attached, form a C₅₋₇ cycloalkyloptionally substituted with one or more R₁₈. In another embodiment, R₃and R₄, together with the carbon atoms to which they are attached, forma 5- to 7-membered heterocycloalkyl ring optionally substituted with oneor more R₁₈. In another embodiment, R₃ and R₄, together with the carbonatoms to which they are attached, form a C₆₋₁₀ aryl ring optionallysubstituted with one or more R₁₈. In another embodiment, R₃ and R₄,together with the carbon atoms to which they are attached, form a 5- to7-membered heteroaryl ring optionally substituted with one or more R₁₈.

In some embodiments of the Formulae above, R₅ is H, D, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, 3- to 7-memberedheterocycloalkyl, NH₂, C₁₋₄ alkylamino, or C₁₋₄ dialkylamino, whereinthe C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, and 3- to7-membered heterocycloalkyl are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH. In anotherembodiment, R₅ is H, D, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, 3- to 7-memberedheterocycloalkyl, NH₂, C₁₋₄ alkylamino, or C₁₋₄ dialkylamino, whereinthe C₁₋₄ alkyl, C₃₋₇ cycloalkyl, and 3- to 7-membered heterocycloalkylare optionally substituted with one or more substituents independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl,halogen, NR₁₄R₁₅, CN, NO₂, and OH. In another embodiment, R₅ is H, D,C₁₋₄ alkyl, NH₂, C₁₋₄ alkylamino, or C₁₋₄ dialkylamino, wherein the C₁₋₄alkyl is optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH. In another embodiment, R₅is H, D, C₁₋₄ alkyl, NH₂, C₁₋₄ alkylamino, or C₁₋₄ dialkylamino. Inanother embodiment, R₅ is H, D, C₁₋₄ alkyl, or C₁₋₄ dialkylamino. Inanother embodiment, R₅ is H, C₁₋₄ alkyl, or C₁₋₄ dialkylamino.

In some embodiments of the Formulae above, R₆ is H, D, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, 3- to 7-memberedheterocycloalkyl, NH₂, C₁₋₄ alkylamino, or C₁₋₄ dialkylamino, whereinthe C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, and 3- to7-membered heterocycloalkyl are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH. In anotherembodiment, R₆ is H, D, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, 3- to 7-memberedheterocycloalkyl, NH₂, C₁₋₄ alkylamino, or C₁₋₄ dialkylamino, whereinthe C₁₋₄ alkyl, C₃₋₇ cycloalkyl, and 3- to 7-membered heterocycloalkylare optionally substituted with one or more substituents independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl,halogen, NR₁₄R₁₅, CN, NO₂, and OH. In another embodiment, R₆ is H, D,C₁₋₄ alkyl, NH₂, C₁₋₄ alkylamino, or C₁₋₄ dialkylamino, wherein the C₁₋₄alkyl is optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH. In another embodiment, R₆is H, D, C₁₋₄ alkyl, NH₂, C₁₋₄ alkylamino, or C₁₋₄ dialkylamino. Inanother embodiment, R₆ is H, D, C₁₋₄ alkyl, or C₁₋₄ dialkylamino. Inanother embodiment, R₆ is H, D, or C₁₋₄ alkyl. In another embodiment, R₆is H, or C₁₋₄ alkyl.

In some embodiments of the Formulae above, R₅ and R₆ together with thecarbon atom to which they are attached form an oxo group. In anotherembodiment, R₅ and R₆ together with the carbon atom to which they areattached form a C₃₋₇ cycloalkyl. In yet another embodiment, R₅ and R₆together with the carbon atom to which they are attached form a 3- to7-membered heterocycloalkyl ring.

In some embodiments of the Formulae above, R₇ is H, D, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, 3- to 7-memberedheterocycloalkyl, or NH₂, wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₃₋₇ cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅,CN, NO₂, and OH. In another embodiment, R₇ is H, D, C₁₋₄ alkyl, C₂₋₄alkenyl, C₃₋₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, or NH₂,wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₃₋₇ cycloalkyl, andheterocycloalkyl are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH. In anotherembodiment, R₇ is H, D, C₁₋₄ alkyl, C₂₋₄ alkenyl, or NH₂, wherein theC₁₋₄ alkyl and C₂₋₄ alkenyl are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH. In anotherembodiment, R₇ is H, D, C₁₋₄ alkyl, or NH₂, wherein the C₁₋₄ alkyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl,halogen, NR₁₄R₁₅, CN, NO₂, and OH. In another embodiment, R₇ is H, D,C₁₋₄ alkyl, or NH₂. In another embodiment, R₇ is H, D, or C₁₋₄ alkyl. Inanother embodiment, R₇ is H or C₁₋₄ alkyl.

In some embodiments of the Formulae above, R₈ is H, D, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, 3- to 7-memberedheterocycloalkyl, or NH₂, wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₃₋₇ cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅,CN, NO₂, and OH. In another embodiment, R₈ is H, D, C₁₋₄ alkyl, C₂₋₄alkenyl, C₃₋₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, or NH₂,wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₃₋₇ cycloalkyl, andheterocycloalkyl are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH. In anotherembodiment, R₈ is H, D, C₁₋₄ alkyl, C₂₋₄ alkenyl, or NH₂, wherein theC₁₋₄ alkyl and C₂₋₄ alkenyl are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH. In anotherembodiment, R₈ is H, D, C₁₋₄ alkyl, or NH₂, wherein the C₁₋₄ alkyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl,halogen, NR₁₄R₁₅, CN, NO₂, and OH. In another embodiment, R₈ is H, D,C₁₋₄ alkyl, or NH₂. In another embodiment, R₈ is H, D, or C₁₋₄ alkyl. Inanother embodiment, R₈ is H or C₁₋₄ alkyl.

In some embodiments of the Formulae above, R₇ and R₈, together with thecarbon atom to which they are attached, form a C₅₋₇ cycloalkyl ringoptionally substituted with one or more R₁₉. In another embodiment, R₇and R₈, together with the carbon atom to which they are attached, form a5- to 7-membered heterocycloalkyl ring optionally substituted with oneor more R₁₉. In another embodiment, R₇ and R₈, together with the carbonatom to which they are attached, form a C₆₋₁₀ aryl ring optionallysubstituted with one or more R₁₉. In another embodiment, R₇ and R₈,together with the carbon atom to which they are attached, form a 5- to7-membered heteroaryl ring optionally substituted with one or more R₁₉.

In some embodiments of the Formulae above, R₉ is H, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, —C(O)R₁₂, C₃₋₇ cycloalkyl, or 3- to 7-memberedheterocycloalkyl, wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₃₋₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl,halogen, NR₁₄R₁₅, CN, NO₂, and OH. In another embodiment, R₉ is H, C₁₋₄alkyl, —C(O)R₁₂, C₃₋₇ cycloalkyl, or 3- to 7-membered heterocycloalkyl,wherein the C₁₋₄ alkyl, C₃₋₇ cycloalkyl, and 3- to 7-memberedheterocycloalkyl are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, halogen, NR₁₄R₁₅, CN, NO₂, andOH. In another embodiment, R₉ is H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, or 3-to 7-membered heterocycloalkyl, wherein the C₁₋₄ alkyl, C₃₋₇ cycloalkyl,and 3- to 7-membered heterocycloalkyl are optionally substituted withone or more substituents independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, halogen,NR₁₄R₁₅, CN, NO₂, and OH. In another embodiment, R₉ is H, C₁₋₄ alkyl,C₃₋₇ cycloalkyl, or 3- to 7-membered heterocycloalkyl. In anotherembodiment, R₉ is C₁₋₄ alkyl, or 3- to 7-membered heterocycloalkyl. Inanother embodiment, R₉ is H, C₁₋₄ alkyl, or 3- to 7-memberedheterocycloalkyl.

In some embodiments of the Formulae above, R₁₀ is H, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, NR₁₄R₁₅, C₃₋₇ cycloalkyl, or 3- to 7-memberedheterocycloalkyl, wherein C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore substituents independently selected from the group consisting ofC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, halogen, NR₁₄R₁₅, CN,NO₂, and OH. In another embodiment, R₁₀ is H, C₁₋₄ alkyl, C₂₋₄ alkenyl,or NR₁₄R₁₅, wherein C₁₋₄ alkyl and C₂₋₄ alkenyl are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl,halogen, NR₁₄R₁₅, CN, NO₂, and OH. In another embodiment, R₁₀ is H, C₁₋₄alkyl, or NR₁₄R₁₅, wherein C₁₋₄ alkyl is optionally substituted with oneor more substituents independently selected from the group consisting ofC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, halogen, NR₁₄R₁₅, CN,NO₂, and OH. In another embodiment, R₁₀ is H, C₁₋₄ alkyl, or NR₁₄R₁₅. Inanother embodiment, R₁₀ is H, C₁₋₃ alkyl, or NR₁₄R₁₅.

In some embodiments of the Formulae above, R₁₁ is H, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, NR₁₄R₁₅, C₃₋₇ cycloalkyl, or 3- to 7-memberedheterocycloalkyl, wherein C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore substituents independently selected from the group consisting ofC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, halogen, NR₁₄R₁₅, CN,NO₂, and OH. In another embodiment, R₁₁ is H, C₁₋₄ alkyl, C₂₋₄ alkenyl,or NR₁₄R₁₅, wherein C₁₋₄ alkyl and C₂₋₄ alkenyl are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl,halogen, NR₁₄R₁₅, CN, NO₂, and OH. In another embodiment, R₁₁ is H, C₁₋₄alkyl, or NR₁₄R₁₅, wherein C₁₋₄ alkyl is optionally substituted with oneor more substituents independently selected from the group consisting ofC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, halogen, NR₁₄R₁₅, CN,NO₂, and OH. In another embodiment, R₁₁ is H, C₁₋₄ alkyl, or NR₁₄R₁₅. Inanother embodiment, R₁₁ is H, C₁₋₃ alkyl, or NR₁₄R₁₅.

In some embodiments of the Formulae above, R₁₂ is C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,C₃₋₇ cycloalkyl, or 3- to 7-membered heterocycloalkyl. In anotherembodiment, R₁₂ is C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy,C₃₋₇ cycloalkyl, or 3- to 7-membered heterocycloalkyl. In anotherembodiment, R₁₂ is C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, or C₁₋₄alkoxy. In another embodiment, R₁₂ is C₁₋₄ alkyl, C₂₋₄ alkenyl, or C₁₋₄alkoxy. In another embodiment, R₁₂ is C₁₋₄ alkyl or C₁₋₄ alkoxy. Inanother embodiment, R₁₂ is C₁₋₄ alkyl.

In some embodiments of the Formulae above, R₁₃ is C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,C₃₋₇ cycloalkyl, or 3- to 7-membered heterocycloalkyl. In anotherembodiment, R₁₃ is C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy,C₃₋₇ cycloalkyl, or 3- to 7-membered heterocycloalkyl. In anotherembodiment, R₁₃ is C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, or C₁₋₄alkoxy. In another embodiment, R₁₃ is C₁₋₄ alkyl, C₂₋₄ alkenyl, or C₁₋₄alkoxy. In another embodiment, R₁₃ is C₁₋₄ alkyl or C₁₋₄ alkoxy. Inanother embodiment, R₁₃ is C₁₋₄ alkyl.

In some embodiments of the Formulae above, R₁₂ and R₁₃ together with thephosphorus atom to which they are attached form a 3-8 memberedheterocycloalkyl ring.

In some embodiments of the Formulae above, R₁₄ is H, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₃₋₇ cycloalkyl, or 5- to7-membered heterocycloalkyl. In another embodiment, R₁₄ is H, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, or C₁₋₄ haloalkyl. In anotherembodiment, R₁₄ is C₃₋₇ cycloalkyl, or 5- to 7-memberedheterocycloalkyl. In another embodiment, R₁₄ is H, C₁₋₄ alkyl, or C₁₋₄haloalkyl. In another embodiment, R₁₄ is H or C₁₋₄ alkyl. In anotherembodiment, R₁₄ is H. In another embodiment, R₁₄ is C₁₋₄ alkyl.

In some embodiments of the Formulae above, R₁₅ is H, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₃₋₇ cycloalkyl, or 5- to7-membered heterocycloalkyl. In another embodiment, R₁₅ is H, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, or C₁₋₄ haloalkyl. In anotherembodiment, R₁₅ is C₃₋₇ cycloalkyl, or 5- to 7-memberedheterocycloalkyl. In another embodiment, R₁₅ is H, C₁₋₄ alkyl, or C₁₋₄haloalkyl. In another embodiment, R₁₅ is H or C₁₋₄ alkyl. In anotherembodiment, R₁₅ is H. In another embodiment, R₁₅ is C₁₋₄ alkyl.

In some embodiments of the Formulae above, R₁₄ and R₁₅ together with thenitrogen atom to which they are attached form a 3- to 8-memberedheterocycloalkyl ring optionally substituted with one or moresubstituents independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, halogen, NR₁₆R₁₇, CN, NO₂, andOH.

In some embodiments of the Formulae above, R₁₆ is H or C₁₋₄ alkyl. Inanother embodiment, R₁₆ is H or C₁₋₃ alkyl. In another embodiment, R₁₆is C₁₋₃ alkyl. In another embodiment, R₁₆ is H or methyl. In anotherembodiment, R₁₆ is methyl. In another embodiment, R₁₆ is H.

In some embodiments of the Formulae above, R₁₇ is H or C₁₋₄ alkyl. Inanother embodiment, R₁₇ is H or C₁₋₃ alkyl. In another embodiment, R₁₇is C₁₋₃ alkyl. In another embodiment, R₁₇ is H or methyl. In anotherembodiment, R₁₇ is methyl. In another embodiment, R₁₇ is H.

In some embodiments of the Formulae above, each R₁₈ is independentlyselected from the group consisting of halogen, OH, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, and NR₁₄R₁₅. In another embodiment, each R₁₈is independently selected from the group consisting of halogen, OH, CN,C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, and NR₁₄R₁₅. In another embodiment, each R₁₈is independently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy.In another embodiment, each R₁₈ is independently selected from the groupconsisting of halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy.

In some embodiments of the Formulae above, each R₁₉ is independentlyselected from the group consisting of halogen, OH, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, and NR₁₄R₁₅. In another embodiment, each R₁₉is independently selected from the group consisting of halogen, OH, CN,C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, and NR₁₄R₁₅. In another embodiment, each R₁₉is independently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy.In another embodiment, each R₁₉ is independently selected from the groupconsisting of halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy.

In some embodiments of the Formulae above, R₂₀ is H or C₁₋₄ alkyl. Inanother embodiment, R₂₀ is C₁₋₄ alkyl. In another embodiment, R₂₀ is H.

In some embodiments of the Formulae above, R₂₁ is H or C₁₋₄ alkyl. Inanother embodiment, R₂₁ is C₁₋₄ alkyl. In another embodiment, R₂₁ is H.

In another embodiment, R₂₀ and R₉, when on adjacent atoms, together withthe atoms to which they are attached form a 5- to 7-memberedheterocycloalkyl ring. In another embodiment, R₂₀ and R₉, when onadjacent atoms, together with the atoms to which they are attached forma 5- or 6-membered heterocycloalkyl ring. In another embodiment, R₂₀ andR₉, when on adjacent atoms, together with the atoms to which they areattached form a 6-membered heterocycloalkyl ring.

In some embodiments of the Formulae above, R₁₂ and R₁₃ are C₁₋₆ alkyl.In another embodiment, R₁₂ and R₁₃ are each —CH₃. In yet anotherembodiment, R₁₂ and R₁₃ are each —CH₂CH₃.

In some embodiments of the Formulae above, m is 0 or 1. In anotherembodiment, m is 1 or 2. In another embodiment, m is 0. In anotherembodiment, m is 1. In another embodiment, m is 2.

In some embodiments of the Formulae above, n is 0 or 1. In anotherembodiment, n is 1 or 2. In another embodiment, n is 0. In anotherembodiment, n is 1. In another embodiment, n is 2.

In some embodiments of the Formulae above, the sum of m and n is 0, 1,or 2.

In some embodiments of the Formulae above, q is 0. In anotherembodiment, q is 1. In another embodiment, q is 2. In anotherembodiment, q is 0 or 1. In another embodiment, q is 1 or 2.

In some embodiments of the Formulae above, R₁₆ and R₁₇ are each H.

In some embodiments of the Formulae above, R₄ is H.

In some embodiments of the Formulae above, X₃ is CH₂ or C(CH₃)₂.

In some embodiments of the Formulae above, R₂ is H, halogen, C₁₋₆ alkyl,C₁₋₆ haloalkyl, or C₂₋₆ alkenyl. In another embodiment, R₂ is fluoro,chloro, CF₃, ethyl or ethenyl.

In some embodiments of the Formulae above, R₂ is halogen. In anotherembodiment, R₂ is fluoro or chloro. In yet another embodiment, R₂ isfluoro. In a further embodiment, R₂ is chloro.

In some embodiments of the Formulae above, R₁ is —P(O)(CH₃)₂,—P(O)(CH₂CH₃)₂, or —C(O)(CH₃)₂. In another embodiment, R₁ is —P(O)(CH₃)₂or —P(O)(CH₂CH₃)₂.

In some embodiments of the Formulae above, R₃ is halogen, C₁₋₆ alkyl, orC₁₋₆ alkoxy. In another embodiment, R₃ is methoxy, ethoxy, ethyl,fluoro, or chloro. In yet another embodiment, R₃ is methoxy. In anotherembodiment, R₃ is ethyl. In yet another embodiment, R₃ is fluoro. In afurther embodiment, R₃ is chloro.

In another embodiment, R₅ is H, C₁₋₄ alkyl, or C₁₋₄ dialkylamino; or R₅and R₆ together with the carbon atom to which they are attached form anoxo group.

In some embodiments of the Formulae above, R₃ is C₁₋₆ alkoxy. In anotherembodiment, R₃ is methoxy. In yet another embodiment, R₃ is ethoxy.

In some embodiments of the Formulae above, R₂ is chloro and R₃ is C₁₋₆alkyl, halogen, or C₁₋₆ alkoxy. In another embodiment, R₂ is chloro andR₃ is methoxy.

In some embodiments of the Formulae above, R₃ is methoxy and R₂ is H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, or C₂₋₆ alkenyl. In another embodiment, R₃is methoxy and R₂ is H. In another embodiment, R₃ is methoxy and R₂ isethyl. In yet another embodiment, R₃ is methoxy and R₂ is CH═CH₂. In afurther embodiment, R₃ is methoxy and R₂ is CF₃

In some embodiments of the Formulae above, m+n=0. In another embodiment,m+n=1. In yet another embodiment, m+n=2

In some embodiments of the Formulae above, m is 0 and n is 1. In anotherembodiment, m is 1 and n is 0. In yet another embodiment, m is 0 and nis 2. In another embodiment, m is 0 and n is 0. In yet anotherembodiment, m is 1 and n is 1.

In some embodiments of the Formulae above, R₉ is H, C₁₋₆ alkyl, orheterocycloalkyl. In another embodiment, R₉ is H or C₁₋₆ alkyl. In yetanother embodiment, R₉ is H, methyl, ethyl, or isopropyl. In anotherembodiment, R₉ is H. In yet another embodiment, R₉ is methyl.

In some embodiments of the Formulae above, R₅ and R₆ together with thecarbon atom to which they are attached form an oxo group. In anotherembodiment, R₅ is H and R₆ is H. In yet another embodiment, R₅ is D andR₆ is D.

In some embodiments of the Formulae above, R₅ is H, R₆ is H, and R₉ is Hor C₁₋₆ alkyl. In another embodiment, R₅ is H, R₆ is H, and R₉ is H. Inyet another embodiment, R₅ is H, R₆ is H, and R₉ is methyl. In anotherembodiment, R₅ is H, R₆ is H, and R₉ is ethyl. In a further embodiment,R₅ is H, R₆ is H, and R₉ is isopropyl.

In some embodiments of the Formulae above, R₅ is H, R₆ is H, and R₉ ismethyl. In another embodiment, R₅ is H, R₆ is H, and R₉ isheterocycloalkyl. In yet another embodiment, R₅ is H, R₆ is H, and R₉ isoxetanyl. In yet another embodiment, R₅ is H, R₆ is H, and R₉ ispiperazinyl. In a further embodiment, R₅ is H, R₆ is H, and R₉ ispiperazinyl substituted with —CH₂CH₂OH.

In some embodiments of the Formulae above, R₅ and R₆ together with thecarbon atom to which they are attached form an oxo group and R₉ is H orC₁₋₆ alkyl. In another embodiment, R₅ and R₆ together with the carbonatom to which they are attached form an oxo group and R₉ is H. In yetanother embodiment, R₅ and R₆ together with the carbon atom to whichthey are attached form an oxo group and R₉ is methyl.

In some embodiments of the Formulae above, R₅ is H, R₆ is D, and R₉ ismethyl. In another embodiment, R₅ is H, R₆ is methyl, and R₉ is methyl.

In some embodiments of the Formulae above, R₅ is H and R₆ is C₁₋₆dialkylamino. In another embodiment, R₅ is H and R₆ is dimethylamino.

In some embodiments of the Formulae above, R₂ is chloro, R₃ is methoxy,and R₁₂ and R₁₃ are C₁₋₆ alkyl. In another embodiment, R₂ is chloro, R₃is methoxy, and R₁₂ and R₁₃ are methyl. In yet another embodiment, R₂ ischloro, R₃ is methoxy, and R₁₂ and R₁₃ are ethyl. In another embodiment,R₂ is chloro, R₃ is methoxy, R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 0, and nis 1.

In some embodiments of the Formulae above, R₂ is chloro, R₃ is methoxy,R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 0, n is 1, and X₄ is NR₉. In anotherembodiment, R₂ is chloro, R₃ is methoxy, R₁₂ and R₁₃ are C₁₋₆ alkyl, mis 0, n is 1, X₄ is NR₉, and R₅ and R₆ are each independently H. In yetanother embodiment, R₂ is chloro, R₃ is methoxy, R₁₂ and R₁₃ are C₁₋₆alkyl, m is 0, n is 1, X₄ is NR₉, and R₅ and R₆ are each independentlyH, wherein R₉ is H, C₁₋₆ alkyl, or 3-8 membered heterocycloalkyl.

In another embodiment, R₂ is chloro, R₃ is methoxy, R₁₂ and R₁₃ are C₁₋₆alkyl, m is 0, n is 1, X₄ is NR₉, and R₅ and R₆ are each independentlyH, wherein R₉ is oxetanyl. In yet another embodiment, R₂ is chloro, R₃is methoxy, R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 0, n is 1, X₄ is NR₉, andR₅ and R₆ are each independently H, wherein R₉ is H, methyl, ethyl, orisopropyl.

In another embodiment, R₂ is chloro, R₃ is methoxy, R₁₂ and R₁₃ are C₁₋₆alkyl, m is 0, n is 1, X₄ is NR₉, and R₅ and R₆ are each independentlyH, wherein R₉ is H. In yet another embodiment, R₂ is chloro, R₃ ismethoxy, R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 0, n is 1, X₄ is NR₉, and R₅and R₆ are each independently H, wherein R₉ is methyl. In yet anotherembodiment, R₂ is chloro, R₃ is methoxy, R₁₂ and R₁₃ are C₁₋₆ alkyl, mis 0, n is 1, X₄ is NR₉, and R₅ and R₆ are each independently H, whereinR₉ is ethyl. In another embodiment, R₂ is chloro, R₃ is methoxy, R₁₂ andR₁₃ are C₁₋₆ alkyl, m is 0, n is 1, X₄ is NR₉, and R₅ and R₆ are eachindependently H, wherein R₉ is isopropyl.

In some embodiments of the Formulae above, R₂ is chloro, R₃ is methoxy,R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 0, n is 1, X₄ is NR₉, and R₅ and R₆together with the carbon atom to which they are attached form an oxogroup. In another embodiment, R₂ is chloro, R₃ is methoxy, R₁₂ and R₁₃are C₁₋₆ alkyl, m is 0, n is 1, X₄ is NR₉, and R₅ and R₆ together withthe carbon atom to which they are attached form an oxo group, wherein R₉is H.

In some embodiments of the Formulae above, R₂ is chloro, R₃ is methoxy,R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 0, n is 1, X₄ is NR₉, R₅ is H, and R₆is methyl. In another embodiment, R₂ is chloro, R₃ is methoxy, R₁₂ andR₁₃ are C₁₋₆ alkyl, m is 0, n is 1, X₄ is NR₉, R₅ is H, and R₆ ismethyl, wherein R₉ is methyl.

In some embodiments of the Formulae above, R₂ is chloro, R₃ is methoxy,R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 0, n is 1, X₄ is NR₉, and R₅ and R₆ areeach independently D. In another embodiment, R₂ is chloro, R₃ ismethoxy, R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 0, n is 1, X₄ is NR₉, and R₅and R₆ are each independently D, wherein R₉ is H.

In some embodiments of the Formulae above, R₂ is chloro, R₃ is methoxy,R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 0, n is 1, and X₄ is CR₁₀R₁₁. Inanother embodiment, R₂ is chloro, R₃ is methoxy, R₁₂ and R₁₃ are C₁₋₆alkyl, m is 0, n is 1, and X₄ is CH₂. In yet another embodiment, R₂ ischloro, R₃ is methoxy, R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 0, n is 1, X₄ isCH₂, R₅ is H, and R₆ is C₁₋₆ dialkylamino. In yet another embodiment, R₂is chloro, R₃ is methoxy, R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 0, n is 1, X₄is CH₂, R₅ is H, and R₆ is C₁₋₆ dimethylamino.

In some embodiments of the Formulae above, R₂ is chloro, R₃ is methoxy,R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 1, and n is 0. In another embodiment,R₂ is chloro, R₃ is methoxy, R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 1, n is 0,and R₅ and R₆ are each independently H. In yet another embodiment, R₂ ischloro, R₃ is methoxy, R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 1, n is 0, R₅and R₆ are each independently H, and X₄ is NR₉.

In a further embodiment, R₂ is chloro, R₃ is methoxy, R₁₂ and R₁₃ areC₁₋₆ alkyl, m is 1, n is 0, R₅ and R₆ are each independently H, and X₄is NR₉, wherein R₉ is H, C₁₋₆ alkyl, or 3-8 membered heterocycloalkyl.In another embodiment, R₂ is chloro, R₃ is methoxy, R₁₂ and R₁₃ are C₁₋₆alkyl, m is 1, n is 0, R₅ and R₆ are each independently H, and X₄ isNR₉, wherein R₉ is H or methyl. In another embodiment, R₂ is chloro, R₃is methoxy, R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 1, n is 0, R₅ and R₆ areeach independently H, and X₄ is NR₉, wherein R₉ is H. In anotherembodiment, R₂ is chloro, R₃ is methoxy, R₁₂ and R₁₃ are C₁₋₆ alkyl, mis 1, n is 0, R₅ and R₆ are each independently H, and X₄ is NR₉, whereinR₉ is methyl.

In some embodiments of the Formulae above, R₂ is chloro, R₃ is methoxy,R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 0, and n is 2. In another embodiment,R₂ is chloro, R₃ is methoxy, R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 0, n is 2,and X₄ is NR₉. In yet another embodiment, R₂ is chloro, R₃ is methoxy,R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 0, n is 2, and X₄ is NR₉, wherein R₉ ismethyl. In another embodiment, R₂ is chloro, R₃ is methoxy, R₁₂ and R₁₃are C₁₋₆ alkyl, m is 0, n is 2, X₄ is NR₉, wherein R₉ is methyl, and R₅and R₆ are each independently H. In a further embodiment, R₂ is chloro,R₃ is methoxy, R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 0, n is 2, X₄ is NR₉,wherein R₉ is methyl, and R₅ and R₆ together with the carbon atom towhich they are attached form an oxo group.

In some embodiments of the Formulae above, R₂ is chloro, R₃ is methoxy,R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 0, and n is 0. In another embodiment,R₂ is chloro, R₃ is methoxy, R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 0, n is 0,and X₄ is CR₁₀R₁₁. In yet another embodiment, R₂ is chloro, R₃ ismethoxy, R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 0, n is 0, and X₄ is CH₂. Inanother embodiment, R₂ is chloro, R₃ is methoxy, R₁₂ and R₁₃ are C₁₋₆alkyl, m is 0, n is 0, X₄ is CH₂, R₅ is H, and R₆ is C₁₋₆ dialkylamino.In yet another embodiment, R₂ is chloro, R₃ is methoxy, R₁₂ and R₁₃ areC₁₋₆ alkyl, m is 0, n is 0, X₄ is CH₂, R₅ is H, and R₆ is C₁₋₆dimethylamino.

In some embodiments of the Formulae above, R₃ is C₁₋₆ alkoxy, and R₁₂and R₁₃ are C₁₋₆ alkyl. In another embodiment, R₃ is methoxy, and R₁₂and R₁₃ are C₁₋₆ alkyl. In yet another embodiment, R₃ is methoxy, andR₁₂ and R₁₃ are each independently methyl.

In some embodiments of the Formulae above, R₃ is methoxy, R₁₂ and R₁₃are each independently methyl, m is 0, and n is 1. In anotherembodiment, R₃ is methoxy, R₁₂ and R₁₃ are each independently methyl, mis 0, n is 1, and X₄ is NR₉. In yet another embodiment, R₃ is methoxy,R₁₂ and R₁₃ are each independently methyl, m is 0, n is 1, and X₄ isNR₉, wherein R₉ is methyl. In another embodiment, R₃ is methoxy, R₁₂ andR₁₃ are each independently methyl, m is 0, n is 1, and X₄ is NR₉,wherein R₉ is methyl and R₅ and R₆ are each independently H.

In a further embodiment, R₃ is methoxy, R₁₂ and R₁₃ are eachindependently methyl, m is 0, n is 1, and X₄ is NR₉, wherein R₉ ismethyl, R₅ and R₆ are each independently H, and R₂ is H, halogen, C₁₋₆alkyl, C₂₋₆ alkenyl, or C₁₋₆ haloalkyl. In another embodiment, R₃ ismethoxy, R₁₂ and R₁₃ are each independently methyl, m is 0, n is 1, andX₄ is NR₉, wherein R₉ is methyl, R₅ and R₆ are each independently H, andR₂ is H. In yet another embodiment, R₃ is methoxy, R₁₂ and R₁₃ are eachindependently methyl, m is 0, n is 1, and X₄ is NR₉, wherein R₉ ismethyl, R₅ and R₆ are each independently H, and R₂ is halogen. Inanother embodiment, R₃ is methoxy, R₁₂ and R₁₃ are each independentlymethyl, m is 0, n is 1, and X₄ is NR₉, wherein R₉ is methyl, R₅ and R₆are each independently H, and R₂ is fluoro. In a further embodiment, R₃is methoxy, R₁₂ and R₁₃ are each independently methyl, m is 0, n is 1,and X₄ is NR₉, wherein R₉ is methyl, R₅ and R₆ are each independently H,and R₂ is CF₃. In another embodiment, R₃ is methoxy, R₁₂ and R₁₃ areeach independently methyl, m is 0, n is 1, and X₄ is NR₉, wherein R₉ ismethyl, R₅ and R₆ are each independently H, and R₂ is ethyl. In yetanother embodiment, R₃ is methoxy, R₁₂ and R₁₃ are each independentlymethyl, m is 0, n is 1, and X₄ is NR₉, wherein R₉ is methyl, R₅ and R₆are each independently H, and R₂ is CH═CH₂.

In some embodiments of the Formulae above, R₂ is halogen, and R₁₂ andR₁₃ are C₁₋₆ alkyl. In another embodiment, R₂ is chloro, and R₁₂ and R₁₃are C₁₋₆ alkyl. In yet another embodiment, R₂ is chloro, and R₁₂ and R₁₃are each independently methyl. In another embodiment, R₂ is chloro, andR₁₂ and R₁₃ are each independently ethyl.

In some embodiments of the Formulae above, R₂ is chloro, R₁₂ and R₁₃ areC₁₋₆ alkyl, m is 0, and n is 1. In another embodiment, R₂ is chloro, R₁₂and R₁₃ are C₁₋₆ alkyl, m is 0, n is 1, and X₄ is NR₉. In yet anotherembodiment, R₂ is chloro, R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 0, n is 1,and X₄ is NR₉, wherein R₉ is methyl. In another embodiment, R₂ ischloro, R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 0, n is 1, and X₄ is NR₉,wherein R₉ is methyl, and R₅ and R₆ are each independently H.

In a further embodiment, R₂ is chloro, R₁₂ and R₁₃ are C₁₋₆ alkyl, m is0, n is 1, and X₄ is NR₉, wherein R₉ is methyl, R₅ and R₆ are eachindependently H, and R₃ is halogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy. Inanother embodiment, R₂ is chloro, R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 0, nis 1, and X₄ is NR₉, wherein R₉ is methyl, R₅ and R₆ are eachindependently H, and R₃ is halogen. In yet another embodiment, R₂ ischloro, R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 0, n is 1, and X₄ is NR₉,wherein R₉ is methyl, R₅ and R₆ are each independently H, and R₃ isfluoro. In another embodiment, R₂ is chloro, R₁₂ and R₁₃ are C₁₋₆ alkyl,m is 0, n is 1, and X₄ is NR₉, wherein R₉ is methyl, R₅ and R₆ are eachindependently H, and R₃ is chloro. In a further embodiment, R₂ ischloro, R₁₂ and R₁₃ are C₁₋₆ alkyl, m is 0, n is 1, and X₄ is NR₉,wherein R₉ is methyl, R₅ and R₆ are each independently H, and R₃ isethoxy. In another embodiment, R₂ is chloro, R₁₂ and R₁₃ are C₁₋₆ alkyl,m is 0, n is 1, and X₄ is NR₉, wherein R₉ is methyl, R₅ and R₆ are eachindependently H, and R₃ is ethyl.

In some embodiments of the Formulae above, A is C₆₋₁₀ aryl and X₁ is N.In another embodiment, A is C₆₋₁₀ aryl, X₁ is N, and X₂ is CH. Inanother embodiment, A is C₆₋₁₀ aryl, X₁ is N, X₂ is CH, and R₁ is—P(O)R₁₂R₁₃. In another embodiment, A is C₆₋₁₀ aryl, X₁ is N, X₂ is CH,and R₁ is —P(O)R₁₂R₁₃. In another embodiment, A is C₆₋₁₀ aryl, X₁ is N,X₂ is CH, R₁ is —P(O)R₁₂R₁₃, and R₁₆ is H. In another embodiment, A isC₆₋₁₀ aryl, X₁ is N, X₂ is CH, R₁ is —P(O)R₁₂R₁₃, R₁₆ is H, and R₁₇ isH. In another embodiment, A is C₆₋₁₀ aryl, X₁ is N, X₂ is CH, R₁ is—P(O)R₁₂R₁₃, R₁₆ is H, R₁₇ is H, and R₄ is H, halogen, or NR₁₄R₁₅. Inanother embodiment, A is C₆₋₁₀ aryl, X₁ is N, X₂ is CH, R₁ is—P(O)R₁₂R₁₃, R₁₆ is H, R₁₇ is H, R₄ is H, halogen, or NR₁₄R₁₅ and R₂ isH, halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ alkoxy, 5- to 7-memberedheteroaryl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore halogen. In another embodiment, A is C₆₋₁₀ aryl, X₁ is N, X₂ is CH,R₁ is —P(O)R₁₂R₁₃, R₁₆ is H, R₁₇ is H, R₄ is H, halogen, or NR₁₄R₁₅, andR₂ is halogen.

A second aspect of the invention relates to compounds of Formula (II):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, and tautomer thereof,

wherein:

R₁ is C₁₋₆ alkoxy, CN, NO₂, C(O)NR₁₄R₁₅, SO₂R₁₄, SO₂NR₁₄R₁₅, C(O)R₁₄, orNR₁₆C(O)R₁₄;

R₂ is halogen;

R₃ is C₁₋₆ alkoxy;

R₄ is H or C₁₋₆ alkyl;

R₁₄ and R₁₅ are each independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, or 3- to 7-memberedheterocycloalkyl; or

R₁₄ and R₁₅ together with the nitrogen atom to which they are attachedform a 3- to 8-membered heterocycloalkyl ring optionally substitutedwith one or more substituents each independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, halogen,NR₁₆R₁₇, CN, NO₂, and OH; and

R₁₆ and R₁₇ are each independently H or C₁₋₆ alkyl.

In some embodiments of the Formula (II), R₁ is C(O)NHMe, SO₂-(i-Pr), orSO₂—N(i-Pr)₂.

In some embodiments of the Formula (II), R₂ is Cl.

In some embodiments of the Formula (II), R₃ is methoxy.

In some embodiments of the Formula (II), R₁ is C(O)NHMe, SO₂-(i-Pr), orSO₂—N(i-Pr)₂ and R₂ is Cl.

In some embodiments of the Formula (II), R₂ is Cl and R₃ is methoxy.

In some embodiments of the Formula (II), R₁ is C(O)NHMe, SO₂-(i-Pr), orSO₂—N(i-Pr)₂, R₂ is Cl, and R₃ is methoxy.

Non-limiting illustrative compounds of the invention include:

-   (2-((5-Chloro-2-((6-methoxy-2-methylisoindolin-5-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-1);-   (2-((5-chloro-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-2);-   (2-((5-chloro-2-((8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-3);-   (2-((5-chloro-2-((8-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-4);-   (2-((5-chloro-2-((6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-5);-   5-chloro-N²-(6-chloro-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)-M-(2-dimethylphosphorylphenyl)pyrimidine-2,4-diamine    (I-6);-   5-chloro-N⁴-(2-dimethylphosphorylphenyl)-N²-(6-ethyl-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)pyrimidine-2,4-diamine    (I-7);-   5-chloro-N⁴-(2-dimethylphosphorylphenyl)-N²-(2-methyl-6-vinyl-3,4-dihydro-1H-isoquinolin-7-yl)pyrimidine-2,4-diamine    (I-8);-   N⁸-[5-chloro-4-(2-dimethylphosphorylanilino)pyrimidin-2-yl]-9-methoxy-2,3,4,6,11,11a-hexahydro-1H-benzo[b]quinolizine-8,10-diamine    (I-9);-   5-chloro-N⁴-(2-dimethylphosphorylphenyl)N²-(9-methoxy-2,3,4,6,11,11a-hexahydro-1H-benzo[b]quinolizin-8-yl)pyrimidine-2,4-diamine    (I-10);-   (2-((5-chloro-2-((2-isopropyl-6-m    ethoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-11);-   (2-((5-chloro-2-((2-ethyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphoshine    oxide (I-12);-   (R)-(2-((5-chloro-2-((8-(dimethylamino)-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-13);-   (R)-(2-((5-chloro-2-((3-(dimethylamino)-6-methoxy-2,3-dihydro-1H-inden-5-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-14);-   (S)-(2-((5-chloro-2-((8-(dimethylamino)-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-15);-   (S)-(2-((5-chloro-2-((3-(dimethylamino)-6-methoxy-2,3-dihydro-1H-inden-5-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-16);-   (2-((5-chloro-2-((2-(dimethylamino)-6-methoxy-2,3-dihydro-1H-inden-5-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-17);-   (2-((5-chloro-2-((7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-18);-   (2-((5-chloro-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)diethylphosphine    oxide (I-19);-   (2-((5-chloro-2-((6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)diethylphosphine    oxide (I-20);-   (2-((5-chloro-2-((7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-21);-   (2-((5-bromo-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-22);-   (2-((5-methoxy-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-23);-   (2-((2-((5-bromo-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-24);-   (2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-25);-   (2-((5-fluoro-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-26);-   (2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-27);-   (2-((5-chloro-2-((6-methoxy-1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-28);-   (2-((5-chloro-2-((6-methoxy-1,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-29);-   5-chloro-M-(2-(isopropylsulfonyl)phenyl)-N²-(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine-2,4-diamine    (11-1);-   2-((5-chloro-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)    N,N-dimethylbenzenesulfonamide (11-2);-   2-((5-chloro-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide    (11-3);-   7-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one    (I-33);-   8-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-7-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one    (I-34);-   (2-((5-chloro-2-((7-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-35);-   (2-((5-chloro-2-((6-ethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-36);-   (2-((5-Chloro-2-((6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-37);-   (2-((5-chloro-2-((7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-38);-   (2-((5-chloro-2-((6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl-1,1-d2)amino)pyrimidin-4-yl)amino)phenyl)dimethyl-phosphine    oxide (I-39);-   (2-((5-chloro-2-((6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-40);-   (2-((5-chloro-2-((6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-41);-   (2-((5-Chloro-2-((6-methoxy-2-(oxetan-3-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-42);-   (2-((5-chloro-2-((2-isopropyl-6-methoxy-1,2,3,4-tetrahydroiso-quinolin-7-yl-1,1-d2)amino)pyrimidin-4-yl)amino)phenyl)-dimethylphosphine    oxide (I-43);-   (2-((5-chloro-2-((6-methoxy-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)-dimethylphosphine    oxide (I-44);-   (2-((5-chloro-2-((2-methyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroiso-quinolin-7-yl)amino)-pyrimidin-4-yl)-amino)phenyl)dimethylphosphine    oxide (I-45);-   (2-((2-((6-Methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-vinylpyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-46);-   (2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-47); and-   (2-((5-Ethyl-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine    oxide (I-48).

In another embodiment of the invention, the compounds of Formula (I) areenantiomers. In some embodiments the compounds are the (S)-enantiomer.In other embodiments the compounds are the (R)-enantiomer. In yet otherembodiments, the compounds of Formula (I) may be (+) or (−) enantiomers.

It should be understood that all isomeric forms are included within thepresent invention, including mixtures thereof. If the compound containsa double bond, the substituent may be in the E or Z configuration. Ifthe compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis- or trans configuration. All tautomeric formsare also intended to be included.

Compounds of the invention, and pharmaceutically acceptable salts,hydrates, solvates, stereoisomers and prodrugs thereof may exist intheir tautomeric form (for example, as an amide or imino ether). Allsuch tautomeric forms are contemplated herein as part of the presentinvention.

The compounds of the invention may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of the invention as wellas mixtures thereof, including racemic mixtures, form part of thepresent invention. In addition, the present invention embraces allgeometric and positional isomers. For example, if a compound of theinvention incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention. Each compound herein disclosed includes all the enantiomersthat conform to the general structure of the compound. The compounds maybe in a racemic or enantiomerically pure form, or any other form interms of stereochemistry. The assay results may reflect the datacollected for the racemic form, the enantiomerically pure form, or anyother form in terms of stereochemistry.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of the invention may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of a chiral HPLC column.

It is also possible that the compounds of the invention may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a compound of Formula (I) incorporates a double bond or a fused ring,both the cis- and trans-forms, as well as mixtures, are embraced withinthe scope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.)Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester,” “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The compounds of Formula I may form salts which are also within thescope of this invention. Reference to a compound of the Formula hereinis understood to include reference to salts thereof, unless otherwiseindicated.

The present invention relates to compounds which are modulators of HPK1.In one embodiment, the compounds of the present invention are inhibitorsof HPK1.

The invention is directed to compounds as described herein andpharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof, and pharmaceutical compositionscomprising one or more compounds as described herein, orpharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof.

Method of Synthesizing the Compounds

The compounds of the present invention may be made by a variety ofmethods, including standard chemistry. Suitable synthetic routes aredepicted in the Schemes given below.

The compounds of Formula (I) may be prepared by methods known in the artof organic synthesis as set forth in part by the following syntheticschemes. In the schemes described below, it is well understood thatprotecting groups for sensitive or reactive groups are employed wherenecessary in accordance with general principles or chemistry. Protectinggroups are manipulated according to standard methods of organicsynthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis”, Third edition, Wiley, New York 1999). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selectionprocesses, as well as the reaction conditions and order of theirexecution, shall be consistent with the preparation of compounds ofFormula (I).

Those skilled in the art will recognize if a stereocenter exists in thecompounds of Formula (I). Accordingly, the present invention includesboth possible stereoisomers (unless specified in the synthesis) andincludes not only racemic compounds but the individual enantiomersand/or diastereomers as well. When a compound is desired as a singleenantiomer or diastereomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be affected by any suitable method known in theart. See, for example, “Stereochemistry of Organic Compounds” by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

Preparation of Compounds

The compounds of the present invention can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the present invention can be synthesized usingthe methods described below, together with synthetic methods known inthe art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include butare not limited to those methods described below. Starting materials areeither commercially available or made by known procedures in thereported literature or as illustrated. Compounds of the presentinvention can be synthesized by following the steps outlined in GeneralScheme 1 which comprise the assembling of intermediates 2a and 2b.Starting materials are either commercially available or made by knownprocedures in the reported literature or as illustrated.

wherein R₁-R₆, R₁₆, R₁₇, A, X₁, X₂, X₃, m, and n are defined as inFormula (I).

The general manner of preparing target compounds of Formula (I) by usingintermediates 2a-1 and 2b-1, is outlined above in General Scheme 1.Nucleophilic addition of 2a-1 to 2b-1 and an acid, e.g., hydrochloricacid (HCl), in a solvent (e.g. ethanol (EtOH) and/or 2-methoxyethanol,etc.) optionally at elevated temperature provides the desired product ofFormula (I).

Compounds of Formula (I) and Formula (II) can exist as enantiomeric ordiastereomeric stereoisomers. Enantiomerically pure compounds of Formula(I) and Formula (II) can be prepared using enantiomerically pure chiralbuilding blocks. Alternatively, racemic mixtures of the final compoundsor a racemic mixture of an advanced intermediate can be subjected tochiral purification as described herein below to deliver the desiredenantiomerically pure intermediates or final compounds. In the instanceswhere an advanced intermediate is purified into its individualenantiomers, each individual enantiomer can be carried on separately todeliver the final enantiomerically pure compounds of Formula (I) andFormula (II).

It should be understood that in the description and formula shown above,the various groups R₁-R₆, R₁₆, R₁₇, A, X, X₂, X₃, m, n, and othervariables are as defined above, except where otherwise indicated.Furthermore, for synthetic purposes, the compounds of General Scheme 1are merely representative with elected radicals to illustrate thegeneral synthetic methodology of the compounds of Formula (I) as definedherein.

Methods of Using the Disclosed Compounds

Another aspect of the invention relates to a method of treating adisease or disorder associated with modulation of HPK1. The methodcomprises administering to a patient in need of a treatment for adisease or disorder associated with modulation of HPK1 an effectiveamount the compositions and compounds of Formula (I).

Another aspect of the invention relates to a method of preventing adisease or disorder associated with modulation of HPK1. The methodcomprises administering to a patient in need of a treatment for adisease or disorder associated with modulation of HPK1 an effectiveamount the compositions and compounds of Formula (I).

Another aspect of the invention relates to a method of treating adisease or disorder associated with modulation of HPK1. The methodcomprises administering to a patient in need of a treatment for adisease or disorder associated with modulation of HPK1 an effectiveamount the compositions and compounds of Formula (II).

Another aspect of the invention relates to a method of preventing adisease or disorder associated with modulation of HPK1. The methodcomprises administering to a patient in need of a treatment a disease ordisorder associated with modulation of HPK1 an effective amount thecompositions and compounds of Formula (II).

Another aspect of the invention relates to a method of treating aHPK1-mediated disease or disorder. The method comprises administering toa patient in need of a treatment of a disease or disorder associatedwith modulation of HPK1 an effective amount the compositions andcompounds of Formula (I).

Another aspect of the invention relates to a method of preventing aHPK1-mediated disease or disorder. The method comprises administering toa patient in need of a treatment for diseases or disorders associatedwith modulation of HPK1 an effective amount the compositions andcompounds of Formula (I).

Another aspect of the invention relates to a method of treating aHPK1-mediated disease or disorder. The method comprises administering toa patient in need of a treatment for diseases or disorders associatedwith modulation of HPK1 an effective amount the compositions andcompounds of Formula (II).

Another aspect of the invention relates to a method of preventing aHPK1-mediated disease or disorder. The method comprises administering toa patient in need of a treatment for diseases or disorders associatedwith modulation of HPK1 an effective amount the compositions andcompounds of Formula (II).

In another aspect, the present invention is directed to a method ofinhibiting HPK1. The method involves administering to a patient in needthereof an effective amount of a compound of Formula (I).

In another aspect, the present invention is directed to a method ofinhibiting HPK1. The method involves administering to a patient in needthereof an effective amount of a compound of Formula (II).

Another aspect of the present invention relates to a method of treatinga disease or disorder in a patient associated with the inhibition ofHPK1, the method comprising administering to a patient in need thereofan effective amount of a compound of Formula (I). In one embodiment, thedisease or disorder is selected from the group consisting of cancer,metastasis, inflammation and auto-immune pathogenesis.

Another aspect of the present invention relates to a method ofpreventing a disease or disorder in a patient associated with theinhibition of HPK1, the method comprising administering to a patient inneed thereof an effective amount of a compound of Formula (I).

Another aspect of the present invention relates to a method of treatinga disease or disorder in a patient associated with the inhibition ofHPK1, the method comprising administering to a patient in need thereofan effective amount of a compound of Formula (II).

Another aspect of the present invention relates to a method ofpreventing a disease or disorder in a patient associated with theinhibition of HPK1, the method comprising administering to a patient inneed thereof an effective amount of a compound of Formula (II).

The present invention also relates to the use of an inhibitor of HPK1for the preparation of a medicament used in the treatment, prevention,inhibition or elimination of a disease or disorder mediated by HPK1,wherein the medicament comprises a compound of Formula (I).

The present invention also relates to the use of an inhibitor of HPK1for the preparation of a medicament used in the treatment, prevention,inhibition or elimination of a disease or disorder mediated by HPK1,wherein the medicament comprises a compound of Formula (II).

In another aspect, the present invention relates to a method for themanufacture of a medicament for treating, preventing, inhibiting, oreliminating a disease or disorder mediated by HPK1, wherein themedicament comprises a compound of Formula (I).

In another aspect, the present invention relates to a method for themanufacture of a medicament for treating, preventing, inhibiting, oreliminating a disease or disorder mediated by HPK1, wherein themedicament comprises a compound of Formula (II).

Another aspect of the present invention relates to a compound of Formula(I) for use in the manufacture of a medicament for treating a disease ordisorder associated with inhibiting HPK1.

Another aspect of the present invention relates to a compound of Formula(II) for use in the manufacture of a medicament for treating a diseaseor disorder associated with inhibiting HPK1.

In another aspect, the present invention relates to the use of acompound of Formula (I) in the treatment of a disease or disorderassociated with inhibiting HPK1.

In another aspect, the present invention relates to the use of acompound of Formula (II) in the treatment of a disease or disorderassociated with inhibiting HPK1.

In another aspect, the present invention relates to the use of acompound of Formula (I) in the prevention of a disease or disorderassociated with inhibiting HPK1.

In another aspect, the present invention relates to the use of acompound of Formula (II) in the prevention of a disease or disorderassociated with inhibiting HPK1.

In some embodiments of the methods above, the disease or disorder isselected from the group consisting of cancer, metastasis, inflammationand auto-immune pathogenesis.

Another aspect of the invention relates to a method of treating cancer.The method comprises administering to a patient in need thereof aneffective amount of a compound of Formula (I).

Another aspect of the invention relates to a method of treating cancer.The method comprises administering to a patient in need thereof aneffective amount of a compound of Formula (II).

In some embodiments, the cancer is selected from liposarcoma,neuroblastoma, glioblastoma, bladder cancer, adrenocortical cancer,multiple myeloma, colorectal cancer, non-small cell lung cancer,oropharyngeal cancer, penis cancer, anal cancer, thyroid cancer, vaginalcancer, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphomaand diffuse large B-cell lymphoma.

Another aspect of the invention relates to a method of inducing cellcycle arrest, apoptosis in tumor cells, and/or enhanced tumor-specific Tcell immunity. The method comprises contacting the cells with aneffective amount of a compound of Formula (I).

Another aspect of the invention relates to a method of inducing cellcycle arrest, apoptosis in tumor cells, and/or enhanced tumor-specific Tcell immunity. The method comprises contacting the cells with aneffective amount of a compound of Formula (II).

In one embodiment, the present invention relates to the use of aninhibitor of HPK1 for the preparation of a medicament used in treatment,prevention, inhibition or elimination of a disease or disorderassociated with associated with cancer and metastasis.

In another embodiment, the present invention relates to a compound ofFormula (I) or Formula (II) or a pharmaceutical composition comprising acompound of the present invention and a pharmaceutically acceptablecarrier used for the treatment of cancers including, but not limited to,liposarcoma, neuroblastoma, glioblastoma, bladder cancer, adrenocorticalcancer, multiple myeloma, colorectal cancer, non-small cell lung cancer,oropharyngeal cancer, penis cancer, anal cancer, thyroid cancer, vaginalcancer, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphomaand diffuse large B-cell lymphoma.

In some embodiments, administration of a compound of Formula (I) or apharmaceutical composition comprising a compound of the presentinvention and a pharmaceutically acceptable carrier induces a change inthe cell cycle or cell viability.

In some embodiments, administration of a compound of Formula (II) or apharmaceutical composition comprising a compound of the presentinvention and a pharmaceutically acceptable carrier induces a change inthe cell cycle or cell viability.

Another aspect of the invention relates to a method of treatinginflammation. The method comprises administering to a patient in needthereof an effective amount of a compound of Formula (I).

Another aspect of the invention relates to a method of treatinginflammation. The method comprises administering to a patient in needthereof an effective amount of a compound of Formula (II).

Another aspect of the invention relates to a method of treatingauto-immune pathogenesis. The method comprises administering to apatient in need thereof an effective amount of a compound of Formula(I).

Another aspect of the invention relates to a method of treatingauto-immune pathogenesis. The method comprises administering to apatient in need thereof an effective amount of a compound of Formula(II).

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier. The pharmaceutical acceptable carrier may furtherinclude an excipient, diluent, or surfactant.

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula (II) and apharmaceutically acceptable carrier. The pharmaceutical acceptablecarrier may further include an excipient, diluent, or surfactant.

In one embodiment, are provided methods of treating a disease ordisorder associated with modulation of HPK1 including, cancer,metastasis, inflammation and auto-immune pathogenesis, comprisingadministering to a patient suffering from at least one of said diseasesor disorder a compound of Formula (I).

In one embodiment, are provided methods of treating a disease ordisorder associated with modulation of HPK1 including, cancer,metastasis, inflammation and auto-immune pathogenesis, comprisingadministering to a patient suffering from at least one of said diseasesor disorder a compound of Formula (II).

In one embodiment, are provided methods of treating a disease ordisorder associated with modulation of HPK1 including, cancer andmetastasis, comprising administering to a patient suffering from atleast one of said diseases or disorder a compound of Formula (I).

In one embodiment, are provided methods of treating a disease ordisorder associated with modulation of HPK1 including, cancer andmetastasis, comprising administering to a patient suffering from atleast one of said diseases or disorder a compound of Formula (II).

One therapeutic use of the compounds or compositions of the presentinvention which inhibit HPK1 is to provide treatment to patients orsubjects suffering from cancer, metastasis, inflammation and auto-immunepathogenesis.

Another therapeutic use of the compounds or compositions of the presentinvention which inhibit HPK1 is to provide treatment to patients orsubjects suffering from cancer and metastasis.

The disclosed compounds of the invention can be administered ineffective amounts to treat or prevent a disorder and/or prevent thedevelopment thereof in subjects.

Administration of the disclosed compounds can be accomplished via anymode of administration for therapeutic agents. These modes includesystemic or local administration such as oral, nasal, parenteral,transdermal, subcutaneous, vaginal, buccal, rectal or topicaladministration modes.

Depending on the intended mode of administration, the disclosedcompositions can be in solid, semi-solid or liquid dosage form, such as,for example, injectables, tablets, suppositories, pills, time-releasecapsules, elixirs, tinctures, emulsions, syrups, powders, liquids,suspensions, or the like, sometimes in unit dosages and consistent withconventional pharmaceutical practices. Likewise, they can also beadministered in intravenous (both bolus and infusion), intraperitoneal,subcutaneous or intramuscular form, and all using forms well known tothose skilled in the pharmaceutical arts.

Illustrative pharmaceutical compositions are tablets and gelatincapsules comprising a Compound of the Invention and a pharmaceuticallyacceptable carrier, such as a) a diluent, e.g., purified water,triglyceride oils, such as hydrogenated or partially hydrogenatedvegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil,safflower oil, fish oils, such as EPA or DHA, or their esters ortriglycerides or mixtures thereof, omega-3 fatty acids or derivativesthereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica,talcum, stearic acid, its magnesium or calcium salt, sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and/or polyethylene glycol; for tablets also; c) abinder, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesiumcarbonate, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) adisintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthangum, algic acid or its sodium salt, or effervescent mixtures; e)absorbent, colorant, flavorant and sweetener; f) an emulsifier ordispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g)an agent that enhances absorption of the compound such as cyclodextrin,hydroxypropyl-cyclodextrin, PEG400, PEG200.

Liquid, particularly injectable, compositions can, for example, beprepared by dissolution, dispersion, etc. For example, the disclosedcompound is dissolved in or mixed with a pharmaceutically acceptablesolvent such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form an injectable isotonic solutionor suspension. Proteins such as albumin, chylomicron particles, or serumproteins can be used to solubilize the disclosed compounds.

The disclosed compounds can be also formulated as a suppository that canbe prepared from fatty emulsions or suspensions; using polyalkyleneglycols such as propylene glycol, as the carrier.

The disclosed compounds can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, containing cholesterol, stearylamine orphosphatidylcholines. In some embodiments, a film of lipid components ishydrated with an aqueous solution of drug to a form lipid layerencapsulating the drug, as described in U.S. Pat. No. 5,262,564 which ishereby incorporated by reference in its entirety.

Disclosed compounds can also be delivered by the use of monoclonalantibodies as individual carriers to which the disclosed compounds arecoupled. The disclosed compounds can also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the Disclosedcompounds can be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example, polylactic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked oramphipathic block copolymers of hydrogels. In one embodiment, disclosedcompounds are not covalently bound to a polymer, e.g., a polycarboxylicacid polymer, or a polyacrylate.

Parental injectable administration is generally used for subcutaneous,intramuscular or intravenous injections and infusions. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions or solid forms suitable for dissolving in liquid prior toinjection.

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier. The pharmaceutical acceptable carrier may furtherinclude an excipient, diluent, or surfactant.

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula (II) and apharmaceutically acceptable carrier. The pharmaceutical acceptablecarrier may further include an excipient, diluent, or surfactant.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentpharmaceutical compositions can contain from about 0.1% to about 99%,from about 5% to about 90%, or from about 1% to about 20% of thedisclosed compound by weight or volume.

The dosage regimen utilizing the disclosed compound is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal orhepatic function of the patient; and the particular disclosed compoundemployed. A physician or veterinarian of ordinary skill in the art canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

Effective dosage amounts of the disclosed compounds, when used for theindicated effects, range from about 0.5 mg to about 5000 mg of thedisclosed compound as needed to treat the condition. Compositions for invivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150,250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosedcompound, or, in a range of from one amount to another amount in thelist of doses. In one embodiment, the compositions are in the form of atablet that can be scored.

EXAMPLES

The disclosure is further illustrated by the following examples andsynthesis schemes, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

Analytical Methods, Materials, and Instrumentation

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Proton nuclear magnetic resonance (NMR) spectrawere obtained on Bruker spectrometers at 400 MHz. Spectra are given inppm (δ) and coupling constants, J, are reported in Hertz.Tetramethylsilane (TMS) was used as an internal standard. Mass spectrawere collected using a Waters ZQ Single Quad Mass Spectrometer (ion trapelectrospray ionization (ESI)). Purity and low resolution mass spectraldata were measured using Waters Acquity i-class ultra-performance liquidchromatography (UPLC) system with Acquity Photo Diode Array Detector,Acquity Evaporative Light Scattering Detector (ELSD) and Waters ZQ MassSpectrometer. Data was acquired using Waters MassLynx 4.1 software andpurity characterized by UV wavelength 220 nm, evaporative lightscattering detection (ELSD) and electrospray positive ion (ESI).(Column: Acquity UPLC BEH C18 1.7 m 2.1×50 mm; Flow rate 0.6 mL/min;Solvent A (95/5/0.1%: 10 mM Ammonium Formate/Acetonitrile/Formic Acid),Solvent B (95/5/0.09%: Acetonitrile/Water/Formic Acid); gradient: 5-100%B from 0 to 2 mins, hold 100% B to 2.2 mins and 5% B at 2.21 mins.Abbreviations used in the following examples and elsewhere herein are:

-   -   ACN acetonitrile    -   atm atmosphere    -   br broad    -   BBN 9-borabicyclo[3.3.1]nonane    -   BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)    -   DABCO 1,4-diazabicyclo[2.2.2]octane    -   DAST diethylaminosulfur trifluoride    -   DBU 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine    -   DCM dichloromethane    -   DIPEA N,N-diisopropylethylamine    -   DMA N,N-dimethylacetamide    -   DMF N,N-dimethylformamide    -   DMSO dimethyl sulfoxide    -   dppf 1,1′-bis(diphenylphosphino)ferrocene    -   EDC N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride    -   EI electron ionization    -   ESI electrospray ionization    -   Et ethyl    -   EtOAc ethyl acetate    -   EtOH ethanol    -   GCMS gas chromatography-mass spectrometry    -   h hour(s)    -   HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate    -   HPLC high-performance liquid chromatography    -   LCMS liquid chromatography-mass spectrometry    -   m multiplet    -   Me methyl    -   MeI methyl iodide    -   MeOH methanol    -   MHz megahertz    -   min minutes    -   MS molecular sieves    -   MTBE 2-methoxy-2-methylpropane    -   MW microwave    -   NMR nuclear magnetic resonance    -   ppm parts per million    -   PSI Pounds per square inch    -   SPhos 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl    -   s singlet    -   SM starting material    -   TFA trifluoroacetic acid    -   TLC thin layer chromatography    -   v volume    -   wt weight

Methods for the Synthesis of Compounds of Formula (I) Method A Example1:(2-((5-Chloro-2-((6-methoxy-2-methylisoindolin-5-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide (I-1)

6-Methoxy-2-methylisoindolin-5-amine 49 (87 mg, 0.49 mmol) was combinedwith (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide (154 mg, 0.49 mmol, prepared as described in J. Med. Chem. 2016,59, 4948), 1 mL of 2-methoxyethanol and 0.70 mL HCl solution (1 M inEtOH). The reaction mixture was stirred at 85° C. for 14 h. The reactionmixture was cooled to rt. Volatiles were removed under reduced pressure.The residue was taken up in DCM and saturated sodium carbonate solution.The organic layer was separated and the aqueous phase was extracted withDCM (2×). The organic layers were combined, dried over sodium sulfate,filtered, and concentrated. The residue was purified by flashchromatography on silica gel column with 0 to 10% MeOH/DCM to afford thetitle compound as a light brown solid (32% yield). ¹H NMR (400 MHz,CDCl₃): δ 10.74 (s, 1H), 8.55 (ddd, J=8.5, 4.4, 1.0 Hz, 1H), 8.17 (s,1H), 8.10 (s, 1H), 7.60-7.48 (m, 2H), 7.36-7.27 (m, 1H), 7.15 (tdd,J=7.5, 2.4, 1.1 Hz, 1H), 6.74 (s, 1H), 3.88 (d, J=10.1 Hz, 5H), 3.83 (q,J=1.5 Hz, 2H), 2.59 (s, 3H), 1.83 (d, J=13.2 Hz, 6H). ESI-MS m/z: 458.1[M+H]+.

The compounds in Table 1 were synthesized as described in Method A aboveusing the corresponding aniline intermediates and 4,5-disubstituted2-chloropyrimidines. The preparation of the aniline intermediates isdescribed herein in Examples 49-76. The 2-chloropyrimidine precursorswere synthesized according to literature procedures (J. Med. Chem. 2016,59, 4948). Compounds I-9 and I-10 were additionally purified bypreparative HPLC, (Waters Sunfire C18 column) eluting with a gradient of5 to 55% ACN in water with a 0.1% TFA modifier.

TABLE 1 ESI- Aniline ¹H NMR MS Example Structure intermediate (400 MHz)m/z 2

(CDCl₃) δ 10.76 (s, 1H), 8.56 (dd, J = 4.39, 7.91 Hz, 1H), 8.10 (s, 1H),7.96 (s, 1H), 7.50-7.57 (m, 1H), 7.47 (s, 1H), 7.27- 7.33 (m, 1H), 7.13(ddt, J = 1.00, 2.32, 7.50 Hz, 1H), 6.60 (s, 1H), 3.85 (s, 3H), 3.43 (s,2H), 2.87 (t, J = 5.77 Hz, 2H), 2.64- 2.72 (m, 2H), 2.44 (s, 3H), 1.83(d, J = 13.05 Hz, 6H) 472.2 [M + H]⁺ 3

(CDCl₃) δ10.80 (s, 1H), 8.60 (ddd, J = 8.6, 4.4, 1.1 Hz, 1H), 8.10 (s,1H), 8.06 (s, 1H), 7.55-7.42 (m, 2H), 7.33-7.26 (m, 1H), 7.11 (tdd, J =7.5, 2.4, 1.1 Hz, 1H), 6.65 (s, 1H), 3.86 (s, 3H), 2.84 (ddd, J = 38.2,6.1, 3.7 Hz, 4H), 2.56 (t, J = 9.4 Hz, 4H), 2.37 (s, 3H), 1.83 (d, J =13.1 Hz, 6H) 486.1 [M + H]⁺ 4

(CDCl₃) δ 10.75 (s, 1H), 8.55 (ddd, J = 8.5, 4.4, 1.0 Hz, 1H), 8.05 (d,J = 3.3 Hz, 2H), 7.43 (tdd, J = 5.4, 4.4, 1.4 Hz, 2H), 7.27- 7.20 (m,1H), 7.04 (tdd, J = 7.4, 2.4, 1.1 Hz, 1H), 6.61 (s, 1H), 3.80 (s, 3H),3.68 (s, 2H), 2.98-2.86 (m, 2H), 2.75-2.61 (m, 2H), 2.27 (s, 3H), 1.77(d, J = 13.1 Hz, 6H), 1.67 (p, J = 5.4 Hz, 2H) 486.1 [M + H]⁺ 5

(CDCl₃) δ 10.88 (s, 1H), 8.53 (dd, J = 4.4, 8.2 Hz, 1H), 8.10 (s, 1H),7.87 (d, J = 8.3 Hz, 1H), 7.58- 7.39 (m, 1H), 7.34-7.23 (m, 1H), 7.18(d, J = 2.3 Hz, 1H), 7.11 (ddt, J = 1.0, 2.3, 7.5 Hz, 1H), 6.83 (d, J =11.7 Hz, 1H), 3.44 (s, 2H), 2.85 (t, J = 5.9 Hz, 2H), 2.69-2.62 (m, 2H),2.43 (s, 3H), 1.83 (d, J = 13.2 Hz, 6H) 460.1 [M + H]⁺ 6

(CDCl₃) = 10.90 (s, 1H), 8.55 (dd, J = 4.8, 8.8 Hz, 1H), 8.12 (s, 1H),8.00 (s, 1H), 7.53-7.47 (m, 1H), 7.35-7.30 (m, 2H), 7.21- 7.08 (m, 2H),3.45 (s, 2H), 2.91-2.80 (m, 2H), 2.67 (t , J = 5.9 Hz, 2H), 2.43 (s,3H), 1.86 (s, 3H), 1.83 (s, 3H) 476.4 [M + H]⁺ 7

(CDCl₃) δ 10.95 (s, 1H), 8.67-8.45 (m, 1H), 8.05 (s, 1H), 7.42 (s, 1H),7.37 (t, J = 8.0 Hz, 1H), 7.27- 7.18 (m, 1H), 7.11-7.01 (m, 1H), 6.98(s, 1H), 6.57 (s, 1H), 3.51 (s, 1H), 2.92 (t, J = 6.0 Hz, 2H), 2.72 (t,J = 5.9 Hz, 2H), 2.61 (q, J = 7.6 Hz, 2H), 2.45 (s, 3H), 1.84 (s, 3H),1.81 (s, 3H) 470.4 [M + H]⁺ 8

(CDCl₃) δ 10.96 (s, 1H), 8.56 (dd, J = 8.5, 4.6 Hz, 1H), 8.06 (s, 1H),7.42 (s, 1H), 7.36 (dd, J = 8.7, 7.2 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H),6.86 (dd, J = 17.5, 11.0 Hz, 1H), 6.66 (s, 1H), 5.64 (dd, J = 17.5, 1.4Hz, 1H), 5.34- 5.23 (m, 1H), 3.52 (s, 3H). 2.93 (t, J = 6.0 Hz, 2H),2.71 (t, J = 6.0 Hz, 2H), 2.44 (s, 3H), 1.84 (s, 3H), 1.81 (s, 3H) 468.4[M + H]⁺ 9

(CDC1₃) δ 10.77 (s, 1H), 8.59 (dd, J = 8.5, 4.4 Hz, 1H), 8.10 (s, 1H),7.62- 7.49 (m, 1H), 7.43 (s, 1H), 7.31 (d, J = 3.1 Hz, 1H), 7.17-7.08(m, 1H), 3.76 (s, 3H), 3.68 (s, 2H), 3.61 (d, J = 14.8 Hz, 1H), 3.26 (d,J = 15.2 Hz, 2H), 3.03 (d, J = 11.4 Hz, 2H), 2.52 (dd, J = 15.6, 4.2 Hz,1H), 2.39-2.27 (m, 1H), 2.28- 2.16 (m, OH), 2.14- 2.03 (m, 1H),1.93-1.85 (m, 2H), 1.85 (s, 3H), 1.82 (s, 3H), 1.76-1.66 (m, 2H),1.45-1.34 (m, 2H) 526.6 [M + H]⁺ 10

(CDCl₃) δ 10.71 (s, 1H), 8.54 (dd, J = 8.5, 4.4 Hz, 1H), 7.98 (s, 1H),7.60- 7.46 (m, 2H), 7.30 (ddd, J = 14.1, 7.7, 1.7 Hz, 1H), 7.17-7.08 (m,1H), 6.55 (s, 1H), 3.84 (s, 3H), 3.73- 3.64 (m, 1H), 3.28 (d, J = 14.5Hz, 1H), 3.05 (d, J = 11.3 Hz, 1H), 2.70 (d, J = 7.2 Hz, 2H), 2.24 (s,1H), 2.12 (s, 1H), 1.85 (d, J = 2.6 Hz, 2H), 1.85- 1.79 (m, 2H), 1.71(d, J = 6.0 Hz, 3H), 1.61-1.56 (m, 14H), 1.38 (dd, J = 11.5, 6.8 Hz, 3H)511.7 [M + H]⁺ 11

(CDCl₃) δ 10.75 (s, 1H), 8.57 (dd, J = 8.4, 4.2 Hz, 1H), 8.11 (s, 1H),7.99 (s, 1H), 7.59-7.46 (m, 2H), 7.30 (ddd, J = 14.1,7.7, 1.6 Hz, 1H),7.16-7.07 (m, 1H), 6.59 (s, 1H), 3.84 (s, 3H), 3.57 (s, 2H), 2.92- 2.80(m, 3H), 2.76 (t, J = 5.8 Hz, 2H), 1.84 (d, J = 13.1 Hz, 6H), 1.14 (d, J= 6.6 Hz, 6H) 500.1 [M + H]⁺ 12

(CDCl₃) δ 10.75 (s, 1H), 8.57 (ddd, J = 8.6, 4.4, 1.1 Hz, 1H), 8.11 (s,1H), 7.99 (s, 1H), 7.54 (ddt, J = 8.6, 7.3, 1.4 Hz, 1H), 7.49 (s, 1H),7.30 (ddd, J = 14.0, 7.6, 1.5 Hz, 1H), 7.12 (tdd, J = 7.6, 2.4, 1.1 Hz,1H), 6.59 (s, 1H), 3.85 (s, 3H), 3.47 (s, 2H), 2.86 (t, J = 5.9 Hz, 2H),2.72 (t, J = 5.9 Hz, 2H), 2.56 (q, J = 7.2 Hz, 2H), 1.84 (d, J = 13.2Hz, 6H), 1.19 (t, J = 7.2 Hz, 3H) 486.1 [M + H]⁺ 13

(CDCl₃) δ 10.79 (s, 1H), 8.63 (ddd, J = 8.5, 4.4, 1.0 Hz, 1H), 8.21 (s,1H), 8.11 (s, 1H), 7.45 (ddt, J = 8.6, 7.2, 1.4 Hz, 1H), 7.31-7.21 (m,3H), 7.09 (tdd, J = 7.6, 2.4, 1.1 Hz, 1H), 6.57 (s, 1H), 3.84 (s, 3H),3.64 (t, J = 6.5 Hz, 1H), 2.82-2.59 (m, 2H), 2.13 (s, 6H), 2.04-1.92 (m,1H), 1.90-1.74 (m, 7H), 1.79-1.63 (m, 2H) 500.2 [M + H]⁺ 14

(CDCl₃) δ 10.77 (s, 1H), 8.61 (ddd, J = 8.6, 4.5, 1.1 Hz, 1H), 8.23 (s,1H), 8.11 (s, 1H), 7.53 (ddt, J = 8.7, 7.3, 1.4 Hz, 1H), 7.44 (s, 1H),7.33-7.20 (m, 1H), 7.11 (tdd, J = 7.5, 2.4, 1.1 Hz, 1H), 6.75 (s, 1H),4.21 (dd, J = 7.4, 4.6 Hz, 1H), 3.87 (s, 3H), 2.92 (dt, J = 15.6, 7.6Hz, 1H), 2.78 (ddd, J = 16.1, 8.7, 5.3 Hz, 1H), 2.13 (s, 6H), 2.13-1.98(m, 2H), 1.88-1.77 (m, 6H) 486.1 [M + H]⁺ 15

(CDCl₃) δ 10.79 (s, 1H), 8.62 (ddd, J = 8.6, 4.4, 1.0 Hz, 1H), 8.21 (s,1H), 8.11 (s, 1H), 7.45 (ddt, J = 8.6, 7.2, 1.4 Hz, 1H), 7.31-7.21 (m,1H), 7.25 (s, 1H), 7.09 (tdd, J = 7.5, 2.4, 1.1 Hz, 1H), 6.57 (s, 1H),3.84 (s, 3H), 3.64 (dd, J = 7.8, 5.3 Hz, 1H), 2.82-2.59 (m, 2H), 2.13(s, 6H), 1.98 (tdd, J = 8.2, 6.3, 3.9 Hz, 1H), 1.90- 1.69 (m, 7H),1.73-1.59 (m, 2H) 500.1 [M + H]⁺ 16

(CDCl₃) δ 10.77 (s, 1H), 8.60 (ddd, J = 8.5, 4.4, 1.0 Hz, 1H), 8.23 (s,1H), 8.11 (s, 1H), 7.53 (ddt, J = 8.7, 7.2, 1.5 Hz, 1H), 7.44 (s, 1H),7.33-7.20 (m, 1H), 7.12 (tdd, J = 7.5, 2.4, 1.1 Hz, 1H), 6.75 (s, 1H),4.21 (dd, J = 7.5, 4.5 Hz, 1H), 3.87 (s, 3H), 2.92 (dt, J = 15.6, 7.6Hz, 1H), 2.78 (ddd, J = 16.0, 8.6, 5.2 Hz, 1H), 2.13 (s, 6H), 2.17- 2.00(m, 2H), 1.88-1.77 (m, 6H) 486.1 [M + H]⁺ 17

(CDCl₃) δ 10.78 (s, 1H), 8.59 (ddd, J = 8.5, 4.4, 1.0 Hz, 1H), 8.12 (d,J = 10.2 Hz, 2H), 7.51 (ddt, J = 8.6, 7.3, 1.4 Hz, 1H), 7.48 (s, 1H),7.34-7.24 (m, 1H), 7.12 (tdd, J = 7.5, 2.4, 1.1 Hz, 1H), 6.74 (s, 1H),3.86 (s, 3H), 3.09- 2.83 (m, 5H), 2.32 (s, 6H), 1.83 (d, J = 13.2 Hz,6H) 486.1 [M + H]⁺ 18

(CDCl₃): δ 10.80 (s, 1H), 8.60 (dd, J = 4.3, 8.1 Hz, 1H), 8.11 (s, 1H),8.04 (s, 1H), 7.54-7.48 (m, 1H), 7.47 (s, 1H), 7.30 (dt, J = 1.4, 7.0Hz, 1H), 7.12 (ddt, J = 1.0, 2.4, 7.5 Hz, 1H), 6.52 (s, 1H), 3.84 (s,3H), 3.54 (s, 2H), 2.78 (t, J = 5.8 Hz, 2H), 2.66 (t, J = 5.8 Hz, 2H),2.46 (s, 3H), 1.85 (s, 3H), 1.82 (s, 3H) 472.5 [M + H]⁺ 19

(CDCl₃): δ 10.99 (s, 1H), 8.59 (dd, J = 4.0, 8.4 Hz, 1H), 8.10 (s, 1H),7.97 (s, 1H), 7.57-7.47 (m, 1H), 7.45 (s, 1H), 7.22 (ddd, J = 1.5, 7.7,12.4 Hz, 1H), 7.11 (ddt, J = 1.1, 2.3, 7.5 Hz, 1H), 6.60 (s, 1H), 3.85(s, 3H), 3.44 (s, 2H), 2.87 (t, J = 5.8 Hz, 2H), 2.69 (t, J = 5.8 Hz,2H), 2.45 (s, 3H), 2.13-1.92 (m, 4H), 1.22 (t, J = 7.7 Hz, 3H), 1.18 (t,J = 7.7 Hz, 3H) 500.4 [M + H]⁺ 20

(CDCl₃): δ 11.13 (s, 1H), 8.58 (dd, J = 3.8, 8.2 Hz, 1H), 8.11 (s, 1H),8.00 (s, 1H), 7.49 (tdd, J = 1.3, 7.3, 8.5 Hz, 1H), 7.22 (ddd, J = 1.5,7.8, 12.5 Hz, 1H), 7.14 (s, 1H), 7.11 (ddt, J = 1.0, 2.4, 7.5 Hz, 1H),3.44 (s, 2H), 2.86 (t, J = 5.9 Hz, 2H), 2.66 (t, J = 5.9 Hz, 2H), 2.43(s, 3H), 2.11-1.93 (m, 4H), 1.22 (t, J = 7.7 Hz, 3H), 1.18 (t, J = 7.7Hz, 3H) 504.4 [M + H]⁺ 21

(DMSO-d₆): δ 11.31 (s, 1H), 8.80 (s, 1H), 8.45 (dd, J = 4.6, 8.7 Hz,1H), 8.15 (s, 1H), 7.60-7.51 (m, 2H), 7.42-7.35 (m, 2H), 7.16-7.07 (m,1H), 4.21 (br s, 2H), 2.98 (br s, 2H), 2.83 (br s, 2H), 1.79 (s, 3H),1.76 (s, 3H) 476.3 [M + H]⁺ 22

(DMSO-d₆): δ 10.85 (s, 1H), 8.30 (dd, J = 8.6, 4.2 Hz, 1H), 8.23 (s,1H), 8.07 (s, 1H), 7.59 (ddd, J = 13.7, 7.7, 1.6 Hz, 1H), 7.56 (s, 1H),7.51 (t, J = 7.9 Hz, 1H), 7.22-7.16 (m, 1H), 6.88 (s, 1H), 3.91 (br. s,3H), 3.80 (s, 3H), 3.22 (br. s, 2H), 2.99 (br. s, 2H), 2.74 (s, 3H),1.76 (d, J = 13.5 Hz, 6H) 516.1 [M + H]⁺ 23

(CDCl₃): δ 10.81 (s, 1H), 8.72 (dd, J = 8.5, 4.4 Hz, 1H), 8.41 (s, 1H),8.15 (s, 1H), 7.75 (s, 1H), 7.57- 7.49 (m, 2H), 7.27 (ddd, J = 14.3,7.7, 1.5 Hz, 1H), 7.10 (tdd, J = 7.6, 2.4, 1.1 Hz, 1H), 6.61 (s, 1H),3.93 (s, 3H), 3.87 (s, 5H), 3.11 (t, J = 6.1 Hz, 2H), 3.00 (t, J = 6.1Hz, 2H), 2.68 (s, 3H), 1.84 (d, J = 13.1 Hz, 6H) 468.0 [M + H]⁺ 24

(CDCl₃): δ 10.94 (s, 1H), 8.56 (dd, J = 8.3, 4.2 Hz, 1H), 8.10 (s, 1H),7.72 (d, J = 2.2 Hz, 1H), 7.56 (td, J = 8.6, 1.5 Hz, 1H), 7.29 (ddd, J =14.1, 7.8, 1.5 Hz, 1H), 7.13 (ddt, J = 7.6, 2.3, 1.0 Hz, 1H), 7.10 (s,1H), 6.84 (s, 1H), 3.50 (s, 2H), 2.84 (t, J = 6.0 Hz, 2H), 2.71 (t, J =6.0 Hz, 2H), 2.45 (s, 3H), 1.84 (d, J = 13.2 Hz, 6H). 519.8 [M + H]⁺ 25

(CDCl₃) δ 10.45 (s, 1H), 8.61 (ddd, J = 8.5, 4.4, 1.0 Hz, 1H), 8.11-8.03(m, 2H), 7.51 (ddt, J = 8.7, 7.3, 1.4 Hz, 1H), 7.46 (s, 1H), 7.30-7.19(m, 1H), 7.05 (tdd, J = 7.5, 2.4, 1.0 Hz, 1H), 6.60 (s, 1H), 6.15 (d, J= 5.7 Hz, 1H), 3.85 (s, 3H), 3.53-3.48 (m, 2H), 2.87 (t, J = 5.9 Hz,2H), 2.68 (t, J = 6.0 Hz, 2H), 2.45 (s, 3H), 1.82 (d, J = 13.1 Hz, 6H)502.1 [M + H]⁺ 26

(CDCl₃) δ 11.13 (s, 1H), 8.79-8.71 (m, 1H), 8.03- 7.96 (m, 2H),7.58-7.49 (m, 1H), 7.40 (s, 1H), 7.26 (ddd, J = 14.0, 7.8, 1.6 Hz, 1H),7.10 (tdd, J = 7.6, 2.4, 1.1 Hz, 1H), 6.61 (s, 1H), 3.86 (s, 3H), 3.54-3.42 (m, 2H), 2.88 (t, J = 5.9 Hz, 2H), 2.73-2.60 (m, 2H), 2.45 (s, 3H),1.84 (d, J = 13.2 Hz, 6H) 456.1 [M + H]⁺ 27

(CDCl₃) δ 10.21 (s, 1H), 8.37 (d, J = 1.0 Hz, 1H), 8.27 (dd, 7 = 8.5,4.3 Hz, 1H), 7.88 (s, 1H), 7.70 (s, 1H), 7.52 (ddt, J = 8.5, 7.3, 1.4Hz, 1H), 7.35 (ddd, J = 13.7, 7.7, 1.6 Hz, 1H), 7.18 (tdd, J = 7.5, 2 4,1.1 Hz, 1H), 6.60 (s, 1H), 3.85 (s, 3H), 3.29 (s, 2H), 2.86 (t, J = 5.9Hz, 2H), 2.65 (t, J = 5.9 Hz, 2H), 2.42 (s, 3H), 1.81 (d, J = 13.2 Hz,6H) 506.2 [M + H]⁺ 28

(CDCl₃) δ 10.66 (s, 1H), 8.51 (dd, J = 8.4, 4.4 Hz, 1H), 8.16 (d, J =17.8 Hz, 2H), 7.49 (dd, J = 8.7, 7.2 Hz, 1H), 7.35-7.22 (m, 2H), 7.10(tdd, J = 7.6, 2.4, 1.1 Hz, 1H), 6.52 (s, 1H), 3.85 (s, 3H), 2.90- 2.76(m, 4H), 2.40 (s, 3H), 1.83 (d, J = 13.1 Hz, 6H), 1.27 (s, 6H) 500.2[M + H]⁺ 29

(CDCl₃) δ 10.67 (s, 1H), 8.54-8.46 (m, 1H), 8.09 (d, J = 21.2 Hz, 2H),7.52 (ddt, J = 8.5, 7.2, 1.5 Hz, 1H), 7.45 (s, 1H), 7.37- 7.23 (m, 1H),7.13 (tdd, J = 7.5, 2.4, 1.1 Hz, 1H), 6.56 (s, 1H), 3.85 (s, 3H), 3.47(q, J = 6.6 Hz, 1H), 3.02 (ddd, J = 11.6, 6.4, 5.0 Hz, 1H), 2.89-2.68(m, 2H), 2.69-2.52 (m, 1H), 2.47 (s, 3H), 1.89- 1.77 (m, 6H), 1.28-1.13(m, 3H) 486.1 [M + H]⁺ 30

(CDCl₃) δ 9.45 (s, 1H), 8.54-8.47 (m, 1H), 8.15 (s, 1H), 7.93 (dd, J =8.0, 1.6 Hz, 1H), 7.88 (s, 1H), 7.66 (ddd, J = 8.6, 7.3, 1.7 Hz, 1H),7.51 (s, 1H), 7.27 (ddd, J = 8.4, 6.6, 1.2 Hz, 1H), 6.61 (s, 1H), 3.86(s, 3H), 3.37 (s, 2H), 3.24 (p, J = 6.8 Hz, 1H), 2.88 (dt, J = 11.7, 6.0Hz, 2H), 2.66 (td, J = 5.9, 3.3 Hz, 2H), 2.44 (d, J = 3.3 Hz, 3H) 502.1[M + H]⁺ 31

(CDCl₃) δ 9.27 (s, 1H), 8.47 (dd, J = 8.4, 1.2 Hz, 1H), 8.13 (s, 1H),7.89 (s, 1H), 7.89 (dd, J = 8.0, 1.6 Hz, 1H), 7.61 (ddd, J = 8.7, 7.3,1.6 Hz, 1H), 7.51 (s, 1H), 7.26 (s, 1H), 6.60 (s, 1H), 3.86 (s, 3H),3.37 (s, 2H), 2.87 (t, J = 5.9 Hz, 2H), 2.73 (s, 6H), 2.67 (t, J = 6.0Hz, 2H), 2.44 (s, 3H) 503.1 [M + H]⁺ 32

(CDCl₃) δ 10.92 (s, 1H), 8.62 (dd, J = 8.8, 1.2 Hz, 1H), 8.10 (s, 1H),7.98 (s, 1H), 7.49 (ddd, J = 7.9, 6.2, 4.9 Hz, 3H), 7.13- 7.04 (m, 1H),6.60 (s, 1H), 6.19 (s, 1H), 3.85 (s, 3H), 3.43 (s, 2H), 3.03 (d, J = 4.9Hz, 3H), 2.87 (t, J = 5.9 Hz, 2H), 2.67 (t, J = 5.9 Hz, 2H), 2.43 (s,3H) 453.2 [M + H]⁺ 33

(CDCl₃) δ 10.96-10.80 (m, 1H), 8.81 (s, 1H), 8.68 (dd, J = 4.5, 8.2 Hz,1H), 8.13 (s, 1H), 7.65-7.47 (m, 1H), 7.37 (s, 1H), 1.24 (ddd, J = 1.5,7.7, 14.2 Hz, 1H), 7.12-7.03 (m, 1H), 6.81 (br s, 1H), 6.68 (s, 1H),3.91 (s, 3H), 3.53 (dt, J = 2.8, 6.6 Hz, 2H), 2.93 (t, J = 6.5 Hz, 2H),1.86-1.74 (m, 6H) 472.0 [M + H]⁺ 34

(CDCl₃): δ10.74-10.98 (m, 1H), 8.60 (dd, J = 4.45, 8.22 Hz, 1H), 8.56(s, 1H), 8.11 (s, 1H), 7.47- 7.57 (m, 1H), 7.40 (s, 1H), 7.21-7.29 (m,1H), 7.02- 7.14 (m, 1H), 6.62 (s, 1H), 3.90 (s, 3H), 3.27 (t, J = 6.40Hz, 2H), 3.19 (s, 3H), 2.74 (t, J = 7.09 Hz, 2H), 2.03 (t, J = 6.71 Hz,2H), 1.81 (d, J = 13.18 Hz, 6H) 500.1 [M + H]⁺ 35

(CDCl₃): δ 10.74-10.98 (m, 1H), 8.60 (dd, J = 4.45, 8.22 Hz, 1H), 8.56(s, 1H), 8.11 (s, 1H), 7.47- 7.57 (m, 1H), 7.40 (s, 1H), 7.21-7.29 (m,1H), 7.02- 7.14 (m, 1H), 6.62 (s, 1H), 3.90 (s, 3H), 3.27 (t, J = 6.40Hz, 2H), 3.19 (s, 3H), 2.74 (t, J = 7.09 Hz, 2H), 2.03 (t, J = 6.71 Hz,2H), 1.81 (d, J = 13.18 Hz, 6H) 486.2 [M + H]⁺ 36

(CDCl₃): δ 10.91-10.44 (m, 1H), 8.49 (dd, J = 4.4, 8.2 Hz, 1H), 8.03 (s,1H), 7.89 (s, 1H), 7.51-7.40 (m, 2H), 7.24 (dt, J = 1.4, 7.0 Hz, 1H),7.05 (ddt, J = 1.0, 2.3, 7.5 Hz, 1H), 6.52 (s, 1H), 4.00 (d, J = 7.0 Hz,2H), 3.33 (s, 2H), 2.83-2.75 (m, 2H), 2.66- 2.56 (m, 2H), 2.41-2.33 (m,3H), 1.76 (d, J = 13.2 Hz, 6H), 1.37 (t, J = 7.0 Hz, 3H) 486.2 [M + H]⁺

Method B Example 37:(2-((5-Chloro-2-((6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide (I-37)

Step 1. 7-Nitro-6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline (37b)

6-(Trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride 37a(400 mg, 1.68 mmol, 1.0 eq) in 4 mL sulfuric acid was cooled to 0° C.Guanidine nitrate (205 mg, 1.68 mmol, 1.0 eq) was added while stirring,and the mixture was stirred from 0° C. to r.t. over 1 h. The reactionwas then quenched with ice, basified with saturated aq. K₂CO₃ solution,and extracted with DCM. Organics were dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified by flashcolumn chromatography on silica (0 to 10% MeOH:EtOAc) to afford7-nitro-6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline 37b as acolorless solid.

Step 2. tert-Butyl7-nitro-6-(trifluoromethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(37c)

7-Nitro-6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline 37b (220 mg,0.894 mmol, 1.0 eq), di-tert-butyl dicarbonate (254 mg, 1.16 mmol, 1.3eq), and Et₃N (0.16 mL, 1.16 mmol, 1.3 eq) were combined in 20 mL DCMand stirred at r.t. for 5 h. The solution was then washed with brine andorganics were dried over anhydrous magnesium sulfate, filtered, andconcentrated to afford tert-butyl7-nitro-6-(trifluoromethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate37c as a colorless oil.

Step 3. tert-Butyl7-amino-6-(trifluoromethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(37d)

tert-Butyl7-nitro-6-(trifluoromethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate37c (312 mg, 0.901 mmol, 1.0 eq) was dissolved in 5 mL EtOH. 10% Pd/C(19 mg, 0.180 mmol, 0.2 eq) was added and the mixture was stirred underballoon pressure of H₂ for 2 h. The reaction was then filtered throughCelite and the filtrate was concentrated to afford tert-butyl7-amino-6-(trifluoromethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate37d as an off-white solid.

Step 4.(2-((5-Chloro-2-((6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide (I-37)

A flask was charged with tert-butyl7-amino-6-(trifluoromethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate37d (150 mg, 0.474 mmol, 1.0 eq),2,5-dichloro-N-(2-dimethylphosphorylphenyl)pyrimidin-4-amine (165 mg,0.522 mmol, 1.1 eq), Pd(OAc)₂ (11 mg, 0.047 mmol, 0.1 eq), Xantphos (55mg, 0.095 mmol, 0.2 eq), and Cs₂CO₃ (232 mg, 0.711 mmol, 1.5 eq). Theflask was evacuated and backfilled with N₂ three times, then 3 mL DMFwas added. The reaction vessel was sealed and the reaction was stirredunder N₂ for 24 h at 110° C. The reaction was then cooled to r.t.,filtered through Celite, and the filtrate was concentrated. The residuewas purified by flash column chromatography on silica (0 to 10%MeOH:EtOAc) to afford tert-butyl7-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-6-(trifluoromethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylateas a white foam.

This material was dissolved in 5 mL DCM and 2 mL TFA was then addedwhile stirring. The reaction was stirred at r.t. for 2 h and thenconcentrated. The residue was partitioned between DCM and saturated aq.NaHCO₃. Organics were dried over anhydrous magnesium sulfate, filtered,and concentrated. The residue was purified by flash columnchromatography on silica (0 to 20% MeOH:DCM) to afford the titlecompound 1-37 as a white solid. 96% yield. ¹H NMR (400 MHz, CDCl₃) δ11.01 (s, 1H), 8.53 (ddd, J=8.6, 4.5, 1.0 Hz, 1H), 8.10 (s, 1H), 7.81(s, 1H), 7.42 (ddt, J=8.6, 7.3, 1.4 Hz, 1H), 7.34 (s, 1H), 7.32-7.21 (m,1H), 7.10 (tdd, J=7.5, 2.3, 1.0 Hz, 1H), 7.03 (s, 1H), 3.96 (s, 2H),3.16 (t, J=5.9 Hz, 2H), 2.80 (t, J=5.9 Hz, 2H), 1.84 (d, J=13.1 Hz, 6H).ESI-MS m/z: 496.1 [M+H]+.

The compounds in Table 2 were synthesized according to Method B aboveusing the corresponding starting secondary amines shown herein below.

TABLE 2 Starting ¹H NMR (400 MHz, ESI-MS Example Structure secondaryamine CDCl₃) m/z 38

δ 11.05-10.34 (m, 1H), 8.60 (s, 1H), 8.11 (s, 1H), 8.06-7.88 (m, 1H),7.60-7.43 (m, 2H), 7.30 (dt, J = 1.5, 7.0 Hz, 1H), 7.19-7.02 (m, 1H),6.51 (s, 1H), 3.97 (s, 2H), 3.85 (s, 3H), 3.11 (t, J = 6.0 Hz, 2H), 2.65(t, J = 5.8 Hz, 2H), 1.84 (d, J = 13.2 Hz, 6H) 457.1 [M + H]⁺ 39

δ 10.76 (s, 1H), 8.55 (dd, J = 4.3, 8.2 Hz, 1H), 8.11 (s, 1H), 7.97 (s,1H), 7.61-7.44 (m, 2H), 7.30 (dt, J = 1.4, 7.0 Hz, 1H), 7.18-7.08 (m,1H), 6.59 (s, 1H), 3.91-3.82 (m, 3H), 3.15 (t, J = 6.0 Hz, 2H), 2.76 (t,J = 5.9 Hz, 2H), 1.87-1.79 (m, 6H) 460.1 [M + H]⁺ 40

δ 10.66 (s, 1H), 8.44 (ddd, J = 8.5, 4.4, 1.0 Hz, 1H), 8.01 (d, J = 3.5Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.53- 7.34 (m, 2H), 7.28- 7.19 (m,1H), 7.10- 7.02 (m, 1H), 6.71 (d, J = 2.4 Hz, 1H), 4.43 (br s, 1H), 3.85(s, 2H), 3.81 (s, 3H), 2.85 (s, 2H), 1.75 (d, J = 13.2 Hz, 6H), 1.24 (s,6H) 486.1 [M + H]⁺ 41

δ 10.76 (s, 1H), 8.55 (dd, J = 4.3, 8.3 Hz, 1H), 8.11 (s, 1H), 7.96 (s,1H), 7.60-7.46 (m, 2H), 7.36-7.27 (m, 1H), 7.20-7.08 (m, 1H), 6.58 (s,1H), 3.90- 3.77 (m, 5H), 3.13 (t, J = 6.0 Hz, 2H), 2.75 (t, J = 5.9 Hz,2H), 1.83 (d, J = 13.2 Hz, 6H), 1.7 (br s, NH) 457.0 [M + H]⁺

Method C Example 42:(2-((5-Chloro-2-((6-methoxy-2-(oxetan-3-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide (I-42)

To(2-((5-Chloro-2-((6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide 1-41 (50 mg, 0.11 mmol) was added oxetan-3-one (36 mg, 0.5 mmol),2 mL of MeOH and acetic acid (33 mg, 0.55 mmol) followed by carefuladdition of NaBH₃CN (21 mg, 0.33 mmol) at about 0° C. After bubblingceased, the reaction mixture was stirred at rt for 14 h. The resultingmixture was quenched with water and concentrated. The resulting residuewas taken up in DCM and saturated aqueous sodium carbonate solution. Theorganic layer was separated, dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo to afford the title compound I-42 asyellow solid. (71% yield). ¹H NMR (400 MHz, CDCl₃) δ 10.92-10.67 (m,1H), 8.55 (dd, J=4.2, 8.2 Hz, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.55-7.44(m, 2H), 7.31 (dt, J=1.4, 7.0 Hz, 1H), 7.11 (ddt, J=0.9, 2.3, 7.5 Hz,1H), 6.60 (s, 1H), 5.39 (s, 1H), 4.72 (d, J=6.5 Hz, 4H), 3.85 (s, 3H),3.66 (t, J=6.5 Hz, 1H), 3.36 (s, 2H), 2.86 (t, J=5.8 Hz, 2H), 2.58 (t,J=5.9 Hz, 2H), 1.83 (d, J=13.2 Hz, 6H). ESI-MS m/z: 514.2 [M+H]⁺.

The compounds in Table 3 were synthesized according to Method C aboveusing the corresponding secondary amine intermediates and carbonylreagents shown in Table 3 herein below.

TABLE 3 Amine Carbonyl ¹H NMR (400 ESI-MS Example Structureintermediates reagents MHz, CDCl₃) m/z 43

acetone δ 10.47-11.10 (m, 1H), 8.64 (dd, J = 4.45, 7.97 Hz, 1H), 8.11(s, 1H), 7.68 (s, 1H), 7.45-7.57 (m, 1H), 7.34 (s, 1H), 7.22-7.31 (m,1H), 7.09 (ddt, J = 1.00, 2.38, 7.47 Hz, 1H), 6.64-6.71 (m, 1H),3.71-3.90 (m, 7H), 3.21-3.41 (m, 1H), 2.80- 2.93 (m, 4H), 1.83 (d, J =13.18 Hz, 6H), 1.07 (d, J = 6.27 Hz, 6H) 502.2 [M + H]⁺ 44

formaldehyde δ 10.75 (s, 1H), 8.55 (ddd, J = 8.5, 4.4, 1.0 Hz, 1H), 8.10(s, 1H), 7.92 (s, 1H), 7.54 (ddt, J = 8.6, 7.2, 1.4 Hz, 1H), 7.47 (s,1H), 7.35- 7.27 (m, 1H), 7.14 (ddd, J = 7.5, 2.4, 1.1 Hz, 1H), 6.77 (s,1H), 3.87 (s, 3H), 3.37 (s, 2H), 2.37 (d, J = 8.3 Hz, 5H), 1.83 (d, J =13.2 Hz, 6H), 1.30 (s, 6H) 500.2 [M + H]⁺ 45

formaldehyde δ 11.02 (s, 1H), 8.54 (ddd, J = 8.6, 4.5, 1.0 Hz, 1H), 8.10(s, 1H), 7.82 (s, 1H), 7.43 (ddt, J = 8.6, 7.3, 1.4 Hz, 1H), 7.36 (s,1H), 7.32- 7.21 (m, 1H), 7.10 (tdd, J = 7.5, 2.3, 1.1 Hz, 1H), 7.01 (s,1H), 3.52 (s, 2H), 2.92 (t, J = 5.9 Hz, 2H), 2.71 (t, J = 5.9 Hz, 2H),2.44 (s, 3H), 1.84 (d, J = 13.2 Hz, 6H) 510.1 [M + H]⁺

Method D Example 46:(2-((2-((6-Methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-vinylpyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide (I-46)

To(2-((5-Chloro-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide I-2 (136 mg, 0.288mmol) was added potassium phosphate tribasic (61.2 mg, 0.288 mmol),palladium (II) acetate (6.47 mg, 0.0288 mmol), and SPhos (23.7 mg,0.0576 mmol). The reaction flask was evacuated and purged with nitrogenthree times before 1,4-dioxane (2.9 ml) and water (0.29 ml) were added.The reaction mixture was sparged briefly with nitrogen, and4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (58.7 μl, 0.346 mmol)was then added. The reaction mixture was stirred at 100° C. for 15 h.After cooling, the resulting mixture was diluted with dichloromethane(10 ml) and washed with water (5 ml). The aqueous wash was extractedwith dichloromethane (3×3 ml) and the combined organic layers were driedover sodium sulfate, filtered, and concentrated in vacuo. This materialwas purified by column chromatography on silica gel (0 to 20% methanolin dichloromethane) to afford the title compound I-46 as a yellow solid.¹H NMR (400 MHz, CDCl₃): δ 10.53 (s, 1H), 8.60 (dd, J=4.4, 8.3 Hz, 1H),8.26 (s, 1H), 8.06 (s, 1H), 7.56-7.48 (m, 2H), 7.26 (ddd, J=1.6, 7.7,14.1 Hz, 1H), 7.07 (ddt, J=1.0, 2.6, 7.6 Hz, 1H), 6.86 (dd, J=11.0, 17.3Hz, 1H), 6.60 (s, 1H), 5.62 (dd, J=1.3, 17.2 Hz, 1H), 5.33 (dd, J=1.2,11.0 Hz, 1H), 3.88-3.82 (m, 3H), 3.46 (s, 2H), 2.88 (t, J=5.9 Hz, 2H),2.70 (t, J=5.9 Hz, 2H), 2.45 (s, 3H), 1.84 (s, 3H), 1.80 (s, 3H). ESI-MSm/z: 464.5 [M+H]⁺.

Compound I-47 in Table 4 was synthesized as described in Method D above.

TABLE 4 ESI- MS m/z Example Structure Boronic acid Aryl halide ¹H NMR(400 MHz) [M + H]⁺ 47

(CDCl₃): δ 9.53 (s, 1H), 8.22 (dd, J = 8.6, 4.1 Hz, 1H), 8.13 (s, 1H),8.00 (s, 1H), 7.85 (d, J = 0.9 Hz, 1H), 7.65 (d, J = 0.9 Hz, 1H),7.58−7.50 (m, 2H), 7.32 (ddd, J = 13.5, 7.7, 1.6 Hz, 1H), 7.13 (tdd, J =7.6, 2.5, 1.1 Hz, 1H), 6.58 (s, 1H), 3.97 (s, 3H), 3.85 (s, 3H), 3.31(s, 2H), 2.85 (t, J = 5.9 Hz, 2H), 2.65 (t, J = 5.9 Hz, 2H), 2.43 (s,3H), 1.75 (d, J = 13.1 Hz, 6H) 518.5

Example 48:(2-((5-Ethyl-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide (I-48)

To a solution of(2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-vinylpyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide 1-46 (33.0 mg, 0.0712 mmol) in methanol (1.0 ml) was addedpalladium on carbon (10.0 by wt %, 7.58 mg, 0.00712 mmol). The reactionflask was then purged with hydrogen, and stirred at rt for 2 h under ahydrogen atmosphere. The reaction was filtered through a Celite pad andthe pad was washed with methanol. The filtrate was concentrated in vacuoand the obtained residue was purified by column chromatography on silicagel (eluting with 0 to 20% methanol in dichloromethane) to afford thetitle compound 1-48 as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 10.39(br s, 1H), 8.57 (dd, J=4.3, 8.1 Hz, 1H), 8.21 (br s, 1H), 7.97 (s, 1H),7.58-7.50 (m, 2H), 7.29 (ddd, J=1.4, 7.6, 14.0 Hz, 1H), 7.14 (ddt,J=0.9, 2.4, 7.5 Hz, 1H), 6.63 (s, 1H), 3.94 (br. s, 2H), 3.89 (s, 3H),3.24 (br s, 2H), 3.12 (br s, 2H), 2.78 (br s, 3H), 2.62 (q, J=7.5 Hz,2H), 1.85 (s, 3H), 1.82 (s, 3H), 1.29 (t, J=7.5 Hz, 3H). ESI-MS m/z:466.4 [M+H]⁺.

Method E Example 49: 6-Methoxy-2-methylisoindolin-5-amine (49)

Step 1. 5-Methoxy-2-methylisoindoline (49b)

To 5-Methoxyisoindoline 49a (500 mg, 3.15 mmol) was added MeOH (5 mL)and formaldehyde (1.5 mL, 37% in water). The reaction mixture wasstirred at rt for 15 min and then cooled to 0° C. Sodium borohydride(400 mg, 10.05 mmol) was then lowly added and the resulting mixture wasstirred at rt for 3 h. Upon reaction completion, the mixture was cooledto 0° C. and quenched by adding ice. The resulting mixture was stirredat rt for another 30 min and then concentrated concentrate. Theresulting residue was taken up in DCM and water and the organic phasewas separated. The aqueous phase was extracted with DCM (3×) and thecombined organic phases were dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure to afford5-methoxy-2-methylisoindoline 49b. The product was taken on to the nextstep without further purification.

Step 2. 5-Methoxy-2-methyl-6-nitroisoindoline (49c)

To a stirred mixture of 5-methoxy-2-methylisoindoline 49b (550 mg g,3.37 mmol) and concentrated sulfuric acid (10 mL) at 0° C. was addedguanidine nitrate (350 mg, 2.87 mmol). The resulting mixture was stirredat 0° C. for 40 min and then quenched with ice and basified with a 4 Naqueous NaOH solution. The basified solution was extracted with DCM andthe combined organic layers dried over magnesium sulfate, filtered, andconcentrated in vacuo. The resulting residue was purified by flashchromatography on silica column eluting with 0 to 5% MeOH/DCM to afford5-methoxy-2-methyl-6-nitroisoindoline 49c as a solid.

Step 3. 6-Methoxy-2-methylisoindolin-5-amine (49)

To a solution of 5-methoxy-2-methyl-6-nitroisoindoline (290 mg, 1.39mmol) in acetone (5 mL) was added zinc powder (911 mg, 13.9 mmol) and 1mL of saturated aqueous NH₄Cl solution. The reaction mixture wasvigorously stirred at rt for 1 h and the resulting solid was filteredoff through a short pack of celite. The filtrate was collected,concentrated in vacuo, and then was taken up in DCM and diluted aqueousNH₄OH solution. The organic layer was separated, dried over anhydroussodium sulfate, filtered, concentrated in vacuo to give6-methoxy-2-methylisoindolin-5-amine 49 as a solid.

The compounds in Table 5 were synthesized according to Method Edescribed herein above. For the synthesis of Compounds 61 and 62, thenitration step (step 2) was not performed.

TABLE 5 Secondary or primary Example amine Tertiary amine Anilineintermediate 50

51

52

53

54

55

56

57

58

59

60

61

62

The compounds in Table 6 were synthesized in a 2-step sequence accordingto the procedures described in steps 2 and 3 of Example 49. In Example66, two equivalents of guanidine nitrate were used in the nitrationstep.

TABLE 6 Starting Aniline Example Material intermediate 63

64

65

66

67

68

69

70

Examples 71 and 72:8-amino-7-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one(71) and 7-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-amine(72)

Step 1.7-Methoxy-2-methyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one(71b)

To a solution of 7-Methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one71a (2 g, 10.46 mmol) in THF (20 ml) cooled to 0° C. was added slowlyNaH (5.44 g, 13.60 mmol). The resulting mixture was stirred at rt for 15min and then again cooled to 0° C. MeI (2.23 g, 15.69 mmol) was thenadded dropwise and the mixture was stirred at rt for 1 h. The reactionmixture was cooled in an ice bath and quenched with ice water. Volatileswere removed under reduced pressure and the residue was partitionedbetween DCM and water. The organic layer was separated, dried overanhydrous sodium sulfate, filtered, and concentrated to afford7-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one as asolid. The product was taken on to the next step without furtherpurification.

7-Methoxy-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (2.10 g,10.23 mmol) was dissolved in 10 mL of DCM. The mixture was cooled to 0°C. before concentrated H₂SO₄ (1.7 mL) and fuming nitric acid (1.8 mL)were added. The mixture was stirred at 0° C. for 1 h, and then warmed tort and stirred at rt for another 2 h. The resulting mixture was thenquenched with ice and concentrated under reduced pressure. The resultingresidue was purified by flash chromatography on silica gel columneluting with 0 to 100% EtOAc to afford7-methoxy-2-methyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one71b as a solid.

Step 2a.8-Amino-7-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one(71)

7-Methoxy-2-methyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one(100 mg, 0.4 mmol) 71b was combined with 2 mL of acetone followed byaddition of zinc powder (226 mg, 4 mmol) and 0.5 mL of saturated aqueousNH₄Cl solution. The mixture was vigorously stirred at rt for 1 h. Solidwas filtered off through a short pack of celite. The filtrate wascollected, concentrated and then was taken up in DCM and diluted aqueousNH₄OH solution. The organic layer was separated, dried over anhydroussodium sulfate, concentrated to give8-amino-7-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one71.

Step 2b. 7-Methoxy-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-amine(72)

To a solution of7-methoxy-2-methyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one(115 mg, 0.46 mmol) 71b in THF (5 mL) was added borane tetrahydrofurancomplex (1.0 M, 3 mL). The resulting mixture was stirred under refluxfor 14 h and then quenched with the slow addition of MeOH at rt andstirred under reflux for 2 h. Volatiles were removed under reducedpressure and the residue was purified by flash chromatography on silicagel eluting with 0 to 10% MeOH/DCM to afford7-methoxy-2-methyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[c]azepine as oil.Reduction of nitro intermediate,7-methoxy-2-methyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[c]azepine, understandard Zn/NH₄Cl reduction conditions as described in step 2a affordedaniline 72.

Example 73: 6-Ethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine (73)

To a solution of6-fluoro-2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (53c) (270 mg,1.28 mmol) in EtOH (5 mL) was added potassium tert-butoxide (173 mg,1.54 mmol). The mixture was stirred at 85° C. for 3 h and then cooled tort and quenched with ice water. The resulting mixture was stirred at rtfor another 15 min. The resulting solid was collected by filtration,washed with acetone, and then dried under vacuum to afford6-ethoxy-2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline 73a as a solid.Nitro intermediate 73a was directly reduced without purification understandard Zn/NH₄Cl conditions to afford aniline 73.

Example 74: 2-Methyl-6-vinyl-1,2,3,4-tetrahydroisoquinolin-7-amine (74)

6-Chloro-2-methyl-7-nitro-3,4-dihydro-1H-isoquinoline (54c) (200 mg,0.882 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (204 mg,1.32 mmol), palladium (II) acetate (9.9 mg, 0.0442 mmol), SPhos (36.2mg, 0.0882 mmol) and potassium phosphate (562 mg, 2.65 mmol) werecombined in a 5 mL microwave vial and then dioxane (2.0 mL) and water(0.2 mL) were added. The reaction mixture was flushed with argon,sealed, and heated under microwave irradiation at 125° C. for 30minutes. The resulting mixture was cooled to room temperature anddiluted with EtOAc and water. The organic layer was separated andconcentrated directly onto celite for purification by silica gel elutingwith a 0 to 5% MeOH in DCM gradient to afford2-methyl-7-nitro-6-vinyl-3,4-dihydro-1H-isoquinoline 74a as a yellowsolid in 72% yield. Nitro intermediate 74a was reduced under standardZn/NH₄Cl conditions to afford aniline 74.

Example 75: 6-Ethyl-2-methyl-3,4-dihydro-1H-isoquinolin-7-amine (75)

To a solution of 2-methyl-7-nitro-6-vinyl-3,4-dihydro-1H-isoquinoline74a (70 mg, 0.321 mmol) in 2 mL EtOH and 0.1 mL 37% aqueous HCl wasadded 10% Pd/C, (wet basis, 8.24 mg, 2 mol %). The reaction was stirredat room temperature under 100 PSI of hydrogen overnight. The reactionmixture was brought to normal pressure, flushed with nitrogen, and thenfiltered over a pad of celite which was washed with EtOH. The filtratewas concentrated in vacuo to afford the product (75) as an off whitefoam in quantitative yield.

Example 76: 8-Bromo-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-amine (76)

A solution of 2-methyl-7-nitro-3,4-dihydro-1H-isoquinoline 76a (500.0mg, 2.60 mmol) in neat trifluoromethanesulfonic acid (6 mL) was cooledto 0° C. and N-bromosuccinimide (926 mg, 5.20 mmol) was added. Thereaction was heated to 60° C. and stirred for 19 h. MoreN-bromosuccinimide (926 mg) was then added and the reaction mixture wasstirred an additional 5 h at 60° C. The resulting mixture was pouredinto ice (˜50 mL) and stirred until homogeneous. The mixture was dilutedwith 10% (v/v) aqueous sodium thiosulfate (20 mL), stirred at rt for 5min and then treated with 4 M aq. NaOH until the pH of the solutionwas >10. The resulting mixture was extracted with dichloromethane (4×20mL) and the combined organic layers were washed with 10% aq. Na₂S₂O₃ (20mL), saturated aq. NaHCO₃ (2×20 mL), and brine (2×20 mL), dried oversodium sulfate, filtered, and concentrated in vacuo. The product waspurified by preparative HPLC (5 μm XSelect CSH C18 column, 19 mm×100 mm,eluting with 5% to 30% ACN/H₂O buffered with 0.1% formic acid) to afford8-bromo-2-methyl-6-nitro-1,2,3,4-tetrahydroisoquinoline 76b as a yellowsolid. Nitro intermediate 76b was reduced under standard Zn/NH₄Clcondition to afford aniline 76.

Example 77: 6-Methoxy-1,2,3,4-tetrahydroisoquinoline-1,1-d₂ (77)

To a solution of 6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 65a (1.0 g,5.64 mmol) in THF (10 mL) at 0° C. was slowly added LiAlD₄ and thereaction mixture was stirred at 0° C. until bubbling ceased. Theresulting mixture was then stirred under reflux until no startingmaterial was left (approximately 3 h). The reaction mixture was cooledto 0° C. and quenched with sequential addition of 0.4 mL of H₂O, 0.4 mLof 15% aqueous NaOH solution, and 1.2 mL of H₂O. After further stirringat rt for 30 min, the resulting solids were filtered off through celiteand the filtrate was concentrated under reduced pressure. The resultingresidue was partitioned between water and DCM and the organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated to give6-methoxy-1,2,3,4-tetrahydroisoquinoline-1,1-d₂ 77 as an oil.

Method F Example 78:6-Methoxy-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline (78)

To a mixture of 2-(3-methoxyphenyl)-2-methylpropan-1-amine 78a (1 g,5.58 mmol) and formic acid (2.8 mL) at 0° C. was added paraformaldehyde(168 mg, 5.59 mmol) and the reaction mixture was stirred at 50° C. for14 h. The resulting mixture was cooled to rt, diluted with water andextracted with DCM. The aqueous phase was separated, basified with 4 NNaOH solution, and extracted with DCM (5×). The combined organics weredried over anhydrous sodium sulfate, filtered, and concentrated toafford 2-(3-methoxyphenyl)-2-methylpropan-1-amine 78 as an oil.

Compound 79 in Table 7 was synthesized as described in Method F aboveusing amine 79a shown herein below.

TABLE 7 Example Staring amine reagent Tertiary amine intermediate 79

Example 80: 6-Methoxy-1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinoline(80)

To a solution of 6-methoxy-1-methyl-3,4-dihydroisoquinoline 80a (840 mg,4.79 mmol, 1.0 eq) in acetone (20 mL) was added MeI (0.33 mL, 5.27 mmol,1.1 eq) with stirring. The reaction mixture was stirred overnight, andthen concentrated under vacuum to afford6-methoxy-1,2-dimethyl-3,4-dihydroisoquinolin-2-ium iodide 80b as ayellow powder. 6-Methoxy-1,2-dimethyl-3,4-dihydroisoquinolin-2-iumiodide 80b (800 mg, 2.52 mmol, 1.0 eq) was suspended in 8 mL THF andcooled to −70° C. using a dry ice/acetone bath. 3 M methyl magnesiumbromide in Et₂O (2.52 mL, 7.57 mmol, 3.0 eq) was added under N₂ whilestirring. After 1 h, the reaction mixture was gradually warmed to r.t.and stirred for 2-3 days. The mixture was then cooled to 0° C. andcarefully quenched with water. The resulting mixture was extracted withEtOAc, and the combined organic layers were dried over anhydrousmagnesium sulfate, filtered, and concentrated to afford6-methoxy-1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinoline 80 as an orangeoil.

Biochemical Assays Example 81: HPK1 Assay

The enzymatic activity of Wild Type HPK1 (MAP4K1) Kinase was measured inthe presence or absence of an inhibitor compound of the presentdisclosure by preparation of a reaction mixture containing a fluoresceintagged peptide (2 micromolar final concentration), ATP (AdenosineTriphosphate, 500 micromolar final concentration) and Wild Type kinase(6 nM final concentration) in a buffer system comprising 50 mM HEPES(Buffer), 3 mM MgCl₂, 5% w/v Trehalose, 0.01% Brij 35 (Detergent), 0.1%Pluronic F127 (Surfactant), 0.1 mM EDTA (Ethylenediaminetetraaceticacid), 0.1 mM EGTA (ethylene glycol-bis(3-aminoethylether)-N,N,N′,N′-tetraacetic acid) and 1 mM DTT (Dithiothreitol) and ata pH of 7.4. The reactions were quenched by the addition of EDTA to afinal concentration of 25 mM. A Caliper EZ reader was used to measurethe extent of substrate to product conversion.

The peptide substrate used in the HPK1 assay was designed based on theamino acid sequence surrounding serine residue 376 of SLP76-Lymphocytecytosolic protein 2 (a known intracellular substrate of HPK1). Thissequence SSFPQSAsLPPYFSQ was modified as follows for use in Caliperassays of HPK1: the serine residues on either side of serine 376 werereplaced with alanine, three lysine residues were added at theN-terminus and a fluorescein tag (FAM) was attached to the C-terminus toproduce the sequence, FAM-FPQAAsLPPYFAKKK.

Table 8: HPK1 activity of compounds of the invention in the HPK1 assay.++++ indicates an IC₅₀ of less than about 5 nM, +++ indicates an IC₅₀between about 5 nM and about 10 nM, ++ indicates an IC₅₀ between about10 nM and about 100 nM, and + indicates an IC₅₀ greater than about 100nM and less than about 10 μM.

TABLE 8 HPK1 Assay. Method of Example Synthesis IC₅₀ I-1 A ++ I-2 A ++++I-3 A ++ I-4 A ++ I-5 A ++++ I-6 A ++++ I-7 A +++ I-8 A +++ I-9 A ++I-10 A ++++ I-11 A ++++ I-12 A ++++ I-13 A ++ I-14 A +++ I-15 A + I-16A + I-17 A ++ I-18 A ++++ I-19 A ++++ I-20 A ++++ I-21 A ++++ I-22 A++++ I-23 A +++ I-24 A ++++ I-25 A + I-26 A ++ I-27 A +++ I-28 A ++ I-29A ++++ II-1 A ++++ II-2 A ++++ II-3 A +++ I-33 A + I-34 A + I-35 A +I-36 A ++ I-37 B ++ I-38 B ++++ I-39 B ++++ I-40 B ++++ I-41 B ++++ I-42C ++ I-43 C ++++ I-44 C +++ I-45 C + I-46 D ++++ I-47 D + I-48 — +++

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: A is C₆₋₁₀ arylor 5- or 6-membered heteroaryl; X₁ is N or CH; X₂ is N or CH; X₃ isCR₇R₈, NH, O, or S(O)_(q); X₄ is NR₉, O, S(O)_(q) or CR₁₀R₁₁; R₁ is—P(O)R₁₂R₁₃; R₂ is H, D, halogen, OH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₆₋₁₀ aryl, 5- to 7-membered heteroaryl, C₃₋₇cycloalkyl, 3- to 7-membered heterocycloalkyl, CN, NO₂, NR₁₄R₁₅,C(O)NR₁₄R₁₅, C(O)OR₁₄, or NR₁₄C(O)R₁₂, wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₆₋₁₀ aryl, and 5- to 7-memberedheteroaryl are optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH; R₃ is H, D, halogen, OH,CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, or NR₁₄R₁₅ wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₁₋₆ alkoxy are optionally substituted withone or more substituents independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, andOH; R₄ is H, D, halogen, OH, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, or NR₁₄R₁₅ wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅,CN, NO₂, and OH; or R₃ and R₄, together with the carbon atoms to whichthey are attached, form a C₅₋₇ cycloalkyl optionally substituted withone or more R₁₈; or R₃ and R₄, together with the carbon atoms to whichthey are attached, form a 5- to 7-membered heterocycloalkyl ringoptionally substituted with one or more R₁₈; or R₃ and R₄, together withthe carbon atoms to which they are attached, form a C₆₋₁₀ aryl ringoptionally substituted with one or more R₁₈; or R₃ and R₄, together withthe carbon atoms to which they are attached, form a 5- to 7-memberedheteroaryl ring optionally substituted with one or more R₁₈; R₅ and R₆are each independently H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, NH₂, C₁₋₆alkylamino, or C₁₋₆ dialkylamino, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl areoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl,halogen, NR₁₄R₁₅, CN, NO₂, and OH; or R₅ and R₆ together with the carbonatom to which they are attached form an oxo group; or R₅ and R₆ togetherwith the carbon atom to which they are attached form a C₃₋₇ cycloalkyl;or R₅ and R₆ together with the carbon atom to which they are attachedform a 3- to 7-membered heterocycloalkyl ring; R₇ and R₈ are eachindependently H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, 3- to 7-membered heterocycloalkyl, or NH₂, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, andheterocycloalkyl are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, halogen, NR₁₄R₁₅, CN, NO₂, and OH; or R₇ and R₈,together with the carbon atom to which they are attached, form a C₅₋₇cycloalkyl ring optionally substituted with one or more R₁₉; or R₇ andR₈, together with the carbon atom to which they are attached, form a 5-to 7-membered heterocycloalkyl ring optionally substituted with one ormore R₁₉; or R₇ and R₈, together with the carbon atom to which they areattached, form a C₆₋₁₀ aryl ring optionally substituted with one or moreR₁₉; or R₇ and R₈, together with the carbon atom to which they areattached, form a 5- to 7-membered heteroaryl ring optionally substitutedwith one or more R₁₉; R₉ is H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, —C(O)R₁₂, C₃₋₇ cycloalkyl, or 3- to 7-memberedheterocycloalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl,halogen, NR₁₄R₁₅, CN, NO₂, and OH; R₁₀ and R₁₁ are each independently H,D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, NR₁₄R₁₅, C₃₋₇ cycloalkyl, or3- to 7-membered heterocycloalkyl, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl,halogen, NR₁₄R₁₅, CN, NO₂, and OH; R₁₂ and R₁₃ are each independentlyC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₃₋₇ cycloalkyl, or 3- to 7-membered heterocycloalkyl;or R₁₂ and R₁₃ together with the phosphorus atom to which they areattached form a 3-8 membered heterocycloalkyl ring; R₁₄ and R₁₅ are eachindependently H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, or 5- to 7-membered heterocycloalkyl; or R₁₄and R₁₅ together with the nitrogen atom to which they are attached forma 3- to 8-membered heterocycloalkyl ring optionally substituted with oneor more substituents independently selected from the group consisting ofC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, halogen, NR₁₆R₁₇, CN,NO₂, and OH; R₁₆ and R₁₇ are each independently H, D, or C₁₋₆ alkyl;each R₁₈ is independently selected from the group consisting of halogen,OH, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, and NR₁₄R₁₅; each R₁₉is independently selected from the group consisting of halogen, OH, CN,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, C(O)NR₁₄R₁₅, NR₁₄C(O)R₁₂, and NR₁₄R₁₅; R₂₀ and R₂₁ areeach independently H, D, or C₁₋₆ alkyl; or R₂₀ and R₉, when on adjacentatoms, together with the atoms to which they are attached form a 5- to7-membered heterocycloalkyl ring; each m and n is independently 0, 1, or2, wherein the sum of m and n is 0, 1, or 2; and q is 0, 1, or
 2. 2. Thecompound of claim 1, wherein X₁ is N.
 3. The compound of claim 1,wherein X₁ is CH.
 4. The compound of claim 2 or 3, wherein X₂ is CH. 5.The compound of claim 2 or 3, wherein X₂ is N.
 6. The compound of anyone of claims 1-5, wherein X₃ is CR₇R₈.
 7. The compound of any one ofclaims 1-6, wherein A is C₆₋₁₀ aryl.
 8. The compound of any one ofclaims 1-7, wherein A is phenyl.
 9. The compound of any one of claims1-6, wherein A is 5- or 6-membered heteroaryl.
 10. The compound of anyone of claims 1-9, wherein R₁₂ and R₁₃ are C₁₋₆ alkyl.
 11. The compoundof claim 10, wherein R₁₂ and R₁₃ are each —CH₃.
 12. The compound ofclaim 10, wherein R₁₂ and R₁₃ are each —CH₂CH₃.
 13. The compound of anyone of claims 1-12, wherein R₃ is selected from the group consisting ofhalogen, C₁₋₆ alkyl, and C₁₋₆ alkoxy.
 14. The compound of claim 13,wherein R₃ is methoxy, ethoxy, ethyl, fluoro or chloro.
 15. The compoundof claim 14, wherein R₃ is methoxy.
 16. The compound of any one ofclaims 1-15, wherein R₂ is selected from the group consisting of H,halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and C₂₋₆ alkenyl.
 17. The compoundof claim 16, wherein R₂ is fluoro, chloro, CF₃, ethyl or ethenyl. 18.The compound of claim 17, wherein R₂ is fluoro or chloro.
 19. Thecompound of claim 18, wherein R₂ is chloro.
 20. The compound of any oneof claims 1-19, wherein R₃ is methoxy and R₂ is chloro.
 21. The compoundof any one of claims 1-20, wherein m+n=0.
 22. The compound of any one ofclaims 1-20, wherein m+n=1.
 23. The compound of any one of claims 1-20,wherein m+n=2.
 24. The compound of claim 22, wherein m is 0 and n is 1.25. The compound of claim 22, wherein m is 1 and n is
 0. 26. Thecompound of claim 23, wherein m is 0 and n is
 2. 27. The compound of anyone of claims 1-26, wherein X₄ is NR₉.
 28. The compound of any one ofclaims 1-26, wherein X₄ is CR₁₀R₁₁.
 29. The compound of any one ofclaims 1-27, wherein R₉ is selected from the group consisting of H, C₁₋₆alkyl, and heterocycloalkyl.
 30. The compound of claim 29, wherein R₉ isH, methyl, ethyl, or isopropyl.
 31. The compound of claim 30, wherein R₉is methyl.
 32. The compound of any one of claims 1-31, wherein R₅ and R₆together with the carbon atom to which they are attached form an oxogroup.
 33. The compound of any one of claims 1-31, wherein R₅ is H andR₆ is H.
 34. The compound of any one of claims 1-31, wherein R₅ is D andR₆ is D.
 35. The compound of any one of claims 1-34, wherein R₄ is H.36. The compound of any one of claims 1-35, wherein R₁₆ and R₁₇ are eachH.
 37. The compound of claim 1, having Formula (Ia) or (Ib):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.
 38. The compound of claim 1, havingone of the following Formulae (Ic), (Id), or (Ie):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.
 39. The compound of claim 1, havingone of the following Formulae (If), (Ig), (Ih), or (Ii):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.
 40. The compound of any one of claims37-39, wherein R₁₂ and R₁₃ are —CH₃.
 41. The compound of any one ofclaims 37-39, wherein R₁₂ and R₁₃ are —CH₂CH₃.
 42. The compound of anyone of claims 37-41, wherein R₂ is halogen.
 43. The compound of claim42, wherein R₂ is chloro.
 44. The compound of any one of claims 37-43,wherein R₃ is selected from the group consisting of C₁₋₆ alkyl, halogen,and C₁₋₆ alkoxy.
 45. The compound of claim 44, wherein R₃ is chloro. 46.The compound of claim 44, wherein R₃ is methoxy.
 47. The compound of anyone of claims 37-44, wherein R₉ is H or C₁₋₆ alkyl.
 48. The compound ofclaim 47, wherein R₉ is H.
 49. The compound of claim 47, wherein R₉ ismethyl.
 50. The compound of any one of claims 37-49, wherein R₅ is H andR₆ is H.
 51. The compound of any one of claims 37-49, wherein R₅ and R₆together with the carbon atom to which they are attached form an oxogroup.
 52. The compound of any one of claim 37-41, wherein R₃ is methoxyand R₂ is selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆haloalkyl, and C₂₋₆ alkenyl.
 53. The compound of any one of claim 37-42,wherein R₂ is chloro and R₃ is selected from the group consisting ofC₁₋₆ alkyl, halogen, and C₁₋₆ alkoxy.
 54. The compound of claim 52 or53, wherein R₅ is H, R₆ is H, and R₉ is methyl.
 55. The compound of anyone of claims 37-49, wherein R₅ is H, R₆ is H, and R₉ isheterocycloalkyl.
 56. The compound of claim 1, having one of thefollowing Formulae (j) or (Ik):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.
 57. The compound of claim 56, whereinR₉ is H.
 58. The compound of claim 56 or 57, wherein R₅ is H and R₆ isC₁₋₆ dialkylamino.
 59. The compound of claim 58, wherein R₅ is H and R₆is dimethylamino.
 60. The compound of any of claims 1-59, selected fromthe group consisting of:(2-((5-Chloro-2-((6-methoxy-2-methylisoindolin-5-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((5-chloro-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((5-chloro-2-((8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((5-chloro-2-((8-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((5-chloro-2-((6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;5-chloro-N²-(6-chloro-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)-M-(2-dimethylphosphorylphenyl)pyrimidine-2,4-diamine;5-chloro-N⁴-(2-dimethylphosphorylphenyl)-N²-(6-ethyl-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)pyrimidine-2,4-diamine;5-chloro-N⁴-(2-dimethylphosphorylphenyl)-N²-(2-methyl-6-vinyl-3,4-dihydro-1H-isoquinolin-7-yl)pyrimidine-2,4-diamine;N⁸-[5-chloro-4-(2-dimethylphosphorylanilino)pyrimidin-2-yl]-9-methoxy-2,3,4,6,11,11a-hexahydro-1H-benzo[b]quinolizine-8,10-diamine;5-chloro-N⁴-(2-dimethylphosphorylphenyl)N²-(9-methoxy-2,3,4,6,11,11a-hexahydro-1H-benzo[b]quinolizin-8-yl)pyrimidine-2,4-diamine;(2-((5-chloro-2-((2-isopropyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((5-chloro-2-((2-ethyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphoshineoxide;(R)-(2-((5-chloro-2-((8-(dimethylamino)-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(R)-(2-((5-chloro-2-((3-(dimethylamino)-6-methoxy-2,3-dihydro-1H-inden-5-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(S)-2-((5-chloro-2-((8-(dimethylamino)-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(S)-(2-((5-chloro-2-((3-(dimethylamino)-6-methoxy-2,3-dihydro-1H-inden-5-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((5-chloro-2-((2-(dimethylamino)-6-methoxy-2,3-dihydro-1H-inden-5-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((5-chloro-2-((7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((5-chloro-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)diethylphosphineoxide;(2-((5-chloro-2-((6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)diethylphosphineoxide;(2-((5-chloro-2-((7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((5-bromo-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((5-methoxy-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((2-((5-bromo-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((5-fluoro-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((5-chloro-2-((6-methoxy-1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((5-chloro-2-((6-methoxy-1,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;5-chloro-M-(2-(isopropylsulfonyl)phenyl)-N²-(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine-2,4-diamine;2-((5-chloro-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;2-((5-chloro-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide;7-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one;8-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-7-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one;(2-((5-chloro-2-((7-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((5-chloro-2-((6-ethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((5-Chloro-2-((6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((5-chloro-2-((7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((5-chloro-2-((6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl-1,1-d2)amino)pyrimidin-4-yl)amino)phenyl)dimethyl-phosphineoxide;(2-((5-chloro-2-((6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((5-chloro-2-((6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((5-Chloro-2-((6-methoxy-2-(oxetan-3-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((5-chloro-2-((2-isopropyl-6-methoxy-1,2,3,4-tetrahydroiso-quinolin-7-yl-1,1-d2)amino)pyrimidin-4-yl)amino)phenyl)-dimethylphosphineoxide;(2-((5-chloro-2-((6-methoxy-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)-dimethylphosphineoxide;(2-((5-chloro-2-((2-methyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroiso-quinolin-7-yl)amino)-pyrimidin-4-yl)-amino)phenyl)dimethylphosphineoxide;(2-((2-((6-Methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-vinylpyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;(2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide; and(2-((5-Ethyl-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide.
 61. The compound of any one of claims 1-60, wherein at least oneof the available hydrogens is replaced with D.
 62. A pharmaceuticalcomposition comprising a compound of any one of claims 1-60, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable diluent, excipient or carrier.
 63. A method of treating aHPK1-mediated disease or disorder, comprising administering to a subjectin need thereof a therapeutically effective amount of a compound of anyone of claims 1-60, or a pharmaceutically acceptable salt thereof. 64.The method of claim 63, wherein the HPK1-mediated disease or disorder isselected from cancer, metastasis, inflammation, and auto-immunepathogenesis.
 65. A method of treating a HPK1-mediated disease ordisorder, comprising administering to a subject in need thereof atherapeutically effective amount of a compound of Formula (II), or apharmaceutically acceptable salt thereof,

wherein: R₁ is C₁₋₆ alkoxy, CN, NO₂, C(O)NR₁₄R₁₅, SO₂R₁₄, SO₂NR₁₄R₁₅,C(O)R₁₄, or NR₁₆C(O)R₁₄; R₂ is halogen; R₃ is C₁₋₆ alkoxy; R₄ is H orC₁₋₆ alkyl; R₁₄ and R₁₅ are each independently H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, or 3- to7-membered heterocycloalkyl; or R₁₄ and R₁₅ together with the nitrogenatom to which they are attached form a 3- to 8-membered heterocycloalkylring optionally substituted with one or more substituents eachindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ hydroxyalkyl, halogen, NR₁₆R₁₇, CN, NO₂, and OH; and R₁₆and R₁₇ are each independently H or C₁₋₆ alkyl.
 66. The method of claim65, wherein R₁ is C(O)NHMe, SO₂-(i-Pr), or SO₂—N(i-Pr)₂.
 67. The methodof claim 65 or 66, wherein R₂ is Cl.
 68. The method of any of claims65-67, wherein R₃ is methoxy.